Thiazolyl-dihydro-indazole

ABSTRACT

The present invention encompasses compounds of the general formula (1)  
                 
in which  
     R 1  to R 3  are defined as in Claim  1,  which are suitable for treating diseases which are characterized by excessive or anomalous cell proliferation, and their use for producing a pharmaceutical having the abovementioned properties.

The present invention relates to novel thiazolyldihydroindazoles of thegeneral formula (1)

where the radicals R¹ to R³ have the meanings given in the claims andthe description, to their isomers, to processes for preparing thesethiazolyl-dihydroindazoles, and to the use of the latter aspharmaceuticals.

BACKGROUND TO THE INVENTION

The phosphorylation of proteins and lipids is an important cellularregulation mechanism which plays a role in many different biologicalprocesses such as cell proliferation, differentiation, apoptosis,metabolism, inflammation, immune reactions and angiogenesis. More than500 kinases are encoded in the human genome. In general, tyrosineprotein kinases are stimulated by growth factors or other mitogenicsignals and phosphorylate proteins which initiate rapid signaltransmissions. Serine/threonine protein kinases mostly phosphorylateproteins which crosslink and amplify intracellular signals. Lipidkinases are likewise important switching sites in intracellular signalpathways, with these sites linking various biological processes.

A number of protein kinases have already proved to be suitable targetmolecules for therapeutic intervention in a variety of indications, e.g.cancer and inflammatory and autoimmune diseases. Since a high percentageof the genes involved in the development of cancer which have beenidentified thus far encode kinases, these enzymes are attractive targetmolecules for the therapy of cancer in particular.

Phosphatidylinositol 3-kinases (PI3 kinases) are a subfamily of thelipid kinases and catalyse the transfer of a phosphate radical to the 3′position of the inositol ring of phosphoinositides. They play a crucialrole in a large number of cellular processes such as cell growth anddifferentiation processes, the regulation of cytoskeletal changes andthe regulation of intracellular transport processes. The PI3 kinases canbe subdivided into different classes on the basis of their in-vitrospecificity for particular phosphoinositide substrates.

Among the members of the class I PI3 kinases, the α, β and δ PI3 kinases(class IA) are principally activated by receptor tyrosine kinases (RTKs)or soluble tyrosine kinases. On the other hand, the γ PI3 kinase (classIB) is principally activated by Gβγ subunits which are released fromheterotrimeric G proteins following activation of heptahelicalreceptors. As a result of these differences in the coupling to cellsurface receptors, in combination with a more or less restrictedexpression, the 4 class I PI3 kinases inevitably have very differenttasks and functions in the intact organism.

Many independent findings indicate that class IA PI3 kinases areinvolved in uncontrolled processes of cell growth and differentiation.Thus, the first PI3 kinase activity which was detected was associatedwith the transforming activity of viral oncogenes such as the middle Tantigen of polyoma viruses, Src tyrosine kinases or activated growthfactors (Workman, Biochem Soc Trans. 2004; 32(Pt 2):393-6). Akt/PKB,which is activated directly by the lipid products of the class I PI3kinases and in this way transmits the signals into the cell, is found tobe hyperactive in many tumours such as breast cancer and ovarian orpancreatic carcinoma. In addition, it has recently been found that thePIK3 CA gene, which encodes the p110 subunit of PI3Kα, exhibits a highfrequency of mutation in many tumour types such as colon, mammary andlung carcinomas, with some of the mutations being representativelycharacterized as being activating mutations (Samuels et al., Science2004; 304(5670):554).

DETAILED DESCRIPTION OF THE INVENTION

It has now been found, surprisingly, that compounds of the generalformula (I), in which the radicals R¹ to R³ have the meanings givenbelow, act as inhibitors of specific cell cycle kinases. Consequently,the compounds according to the invention can be used, for example, fortreating diseases which are connected to the activity of specific cellcycle kinases and are characterized by excessive or anomalous cellproliferation.

The present invention relates to compounds of the general formula (1)

in which

R¹ is selected from the group consisting of —NHR^(c), —NHC(O)R^(c),—NHC(O)OR^(c), —NHC(O)NR^(c)R^(c) and —NHC(O)SR^(c);

R² is a radical which is optionally substituted by one or more R⁴ andwhich is selected from the group consisting of C₁₋₆alkyl,C₃₋₈cycloalkyl, 3-8-membered heterocycloalkyl, C₆₋₁₀aryl and 5-10-membered heteroaryl;

R³ is a radical which is optionally substituted by one or more R^(e)and/or R^(f) and is selected from the group consisting of C₆₋₁₀aryl and5-10-membered heteroaryl;

R⁴ is a radical selected from the group consisting of R^(a), R^(b) andR^(a) which is substituted by one or more, identical or different, R^(c)and/or R^(b);

each R^(a) is, independently of each other, selected from the groupconsisting of C₁₋₆alkyl, C₃₋₈cycloalkyl, C₄₋₁₁cycloalkylalkyl,C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6-membered heteroalkyl, 3-8-memberedheterocycloalkyl, 4-14-membered heterocycloalkylalkyl, 5-10-memberedheteroaryl and 6-16-membered heteroarylalkyl;

each R^(b) is a suitable radical and in each case selected,independently of each other, from the group consisting of ═O, —OR^(c),C₁₋₃haloalkyloxy, —OCF₃, ═S, —SR^(c), ═NR^(c), ═NOR^(c), —NR^(c)R^(c),halogen, —CF3, —CN, —NC, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(c),—S(O)₂R^(c), —S(O)₂OR^(c), —S(O)NR^(c)R^(c), —S(O)₂NR^(c)R^(c),—OS(O)R^(c), —OS(O)₂R^(c), —OS(O)₂OR^(c), —OS(O)₂NR^(c)R^(c),—C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(c), —C(O)N(R^(g))NR^(c)R^(c),—C(O)N(R^(g))OR^(c), —CN(R^(g))NR^(c)R^(c), —OC(O)R^(c), —OC(O)OR^(c),—OC(O)NR^(c)R^(c), —OCN(R^(g))NR^(c)R^(c), —N(R^(g))C(O)R^(c),—N(R^(g))C(O)R^(c), —N(R^(g))C(S)R^(c), —N(R^(g))S(O)₂R^(c),—N(R^(g))S(O)₂NR^(c)R^(c), —N[S(O)₂]₂R^(c), —N(R^(g))C(O)OR^(c),—N(R^(g))C(O)NR^(c)R^(c), and —N(R^(g))CN(R^(g))NR^(c)R^(c);

each R^(c) is, independently of each other, hydrogen or a radical whichis optionally substituted by one or more, identical or different, R^(d)and/or R^(e) and which is selected from the group consisting ofC₁₋₆alkyl, C₃₋₈cycloalkyl, C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl,C₇₋₁₆arylalkyl, 2-6-membered heteroalkyl, 3-8-membered heterocycloalkyl,4-14-membered heterocycloalkylalkyl, 5-10-membered heteroaryl and6-16-membered heteroarylalkyl,

each R^(d) is, independently of each other, hydrogen or a radical whichis optionally substituted by one or more, identical or different, R^(e)and/or R^(f) and which is selected from the group consisting ofC₁₋₆alkyl, C₃₋₈cycloalkyl, C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl,C₇₋₁₆arylalkyl, 2-6-membered heteroalkyl, 3-8-membered heterocycloalkyl,4-14-membered heterocycloalkylalkyl, 5-10-membered heteroaryl and6-16-membered heteroarylalkyl,

each R^(e) is a suitable radical and in each case selected,independently of each other, from the group consisting of ═O, —OR^(f),C₁₋₃haloalkyloxy, —OCF₃, ═S, —SR^(f), ═NR^(f), ═NOR^(f), —NR^(f)R^(f),halogen, —CF3, —CN, —NC, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(f),—S(O)₂R^(f), —S(O)₂OR^(f), —S(O)NR^(f)R^(f), —S(O)₂NR^(f)R^(f),—OS(O)R^(f), —OS(O)₂R^(f), —OS(O)₂OR^(f), —OS(O)₂NR^(f)R^(f),—C(O)R^(f), —C(O)OR^(f), —C(O)NR^(f)R^(f), —CN(R^(g))NR^(f)R^(f),—OC(O)R^(f), —OC(O)OR^(f), —OC(O)NR^(f)R^(f), —OCN(R^(g))NR^(f)R^(f),—N(R^(g))C(O)R^(f), —N(R^(g))C(S)R^(f), —N(R^(g))S(O)₂R^(f),—N(R^(g))C(O)OR^(f), —N(R^(g))C(O)NR^(f)R^(f), and—N(R^(g))CN(R^(g))NR^(f)R^(f);

each R^(f) is, independently of each other, hydrogen or a radical whichis optionally substituted by one or more, identical or different, R^(g)and which is selected from the group consisting of C₁₋₆alkyl,C₃₋₈cycloalkyl, C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl,2-6-membered heteroalkyl, 3-8-membered heterocycloalkyl, 4-14-memberedheterocycloalkylalkyl, 5-10-membered heteroaryl and 6-16-memberedheteroarylalkyl,

each R^(g) is, independently of each other, hydrogen, C₁₋₆alkyl,C₃₋₈cycloalkyl, C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl,2-6-membered heteroalkyl, 3-8-membered heterocycloalkyl, 4-14-memberedheterocycloalkylalkyl, 5-10-membered heteroaryl and 6-16-memberedheteroarylalkyl, where appropriate in the form of their tautomers, theirracemates, their enantiomers, their diastereomers and their mixtures, aswell as, where appropriate, their pharmacologically harmless acidaddition salts.

One aspect of the invention relates to compounds of the general formula(1) where R³ is a radical which is selected from the group consisting ofphenyl, furyl, pyridyl, pyrimidinyl and pyrazinyl, where appropriatesubstituted by one or more R⁴.

Another aspect of the invention relates to compounds of the generalformula (1) where R³ is pyridyl.

Another aspect of the invention relates to compounds of the generalformula (1) where R¹ is —NHC(O)R^(c).

Another aspect of the invention relates to compounds of the generalformula (1) where R¹ is —NHC(O)CH₃.

One aspect of the invention relates to compounds of formula (A)

where

X is —CH₃, —OR⁴ or —SR⁴, and

Y is phenyl, 5-10-membered heteroaryl or the group —C(O)O, and

R^(y) is hydrogen, —NO₂ or C₁₋₆alkyl and R⁴ is defined as above.

Another aspect of the invention relates to compounds of the generalformula (A) where R⁴ is —C₁₋₆alkyl.

Another aspect of the invention relates to the use of compounds of theformula (A) as synthesis intermediates.

One aspect of the invention relates to compounds of the general formula(1), or their pharmaceutically active salts, as pharmaceuticals.

One aspect of the invention relates to the use of compounds of thegeneral formula (1), or their pharmaceutically active salts, forproducing a pharmaceutical having an antiproliferative effect.

One aspect of the invention relates to a pharmaceutical compositionwhich comprises, as the active compound, one or more compounds of thegeneral formula (1) or their physiologically tolerated salts, whereappropriate in combination with customary auxiliary substances and/orcarrier substances.

Another aspect of the invention relates to the use of compounds of thegeneral formula (1) for producing a pharmaceutical for treating and/orpreventing cancer.

One aspect of the invention relates to a pharmaceutical preparationwhich comprises a compound of the general formula (1) and at least onefurther cytostatic or cytotoxic active substance which differs fromformula (1), where appropriate in the form of their tautomers, theirracemates, their enantiomers, their diastereomers and their mixtures, aswell as, where appropriate, their pharmacologically harmless acidaddition salts.

DEFINITIONS

As used herein, the following definitions apply unless otherwisedescribed.

Alkyl substituents are in each case to be understood as being saturated,unsaturated, straight-chain or branched aliphatic hydrocarbon radicals(alkyl radicals) and comprise both saturated alkyl radicals andunsaturated alkenyl and alkynyl radicals. Alkenyl substituents are ineach case straight-chain or branched, unsaturated alkyl radicals whichpossess at least one double bond. Alkynyl substituents are in each caseto be understood as being straight-chain or branched, unsaturated alkylradicals which possess at least one triple bond.

Heteroalkyl represents straight-chain or branched aliphatic hydrocarbonchains which are interrupted by from 1 to 3 heteroatoms, with it beingpossible for each of the available carbon and nitrogen atoms in theheteroalkyl chain to be optionally substituted, in each caseindependently of each other, and with the heteroatoms being selected, ineach case independently of each other, from the group consisting of O, Nand S (e.g. dimethylaminomethyl, dimethylaminoethyl,dimethyl-aminopropyl, diethylaminomethyl, diethylaminoethyl,diethylaminopropyl, 2-diisopropylaminoethyl, bis-2-methoxyethylamino,[2-(dimethylaminoethyl)-ethylamino]methyl,3-[2-(dimethylaminoethyl)ethylamino]propyl, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, methoxy, ethoxy, propoxy, methoxymethyland 2-methoxyethyl).

Haloalkyl refers to alkyl radicals in which one or more hydrogen atom(s)has/have been replaced by halogen atoms. Haloalkyl includes bothsaturated alkyl radicals and unsaturated alkenyl and alkynyl radicals,such as —CF₃, —CHF₂, —CH₂F, —CF₂CF₃, —CHFCF₃, —CH₂CF₃, —CF₂CH₃, —CHFCH₃,—CF₂CF₂CF₃, —CF₂CH₂CH₃, —CF═CF₂, —CCl═CH₂, —CBr═CH₂, —CI═CH₂, —C≡C—CF₃,—CHFCH₂CH₃ and —CHFCH₂CF₃.

Halogen refers to fluorine, chlorine, bromine and/or iodine atoms.

Cycloalkyl is to be understood as being a monocyclic or bicyclic ringwhere the ring system can be a saturated ring, or else an unsaturated,nonaromatic ring, which can, where appropriate, also contain doublebonds, such as cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, norbornyl andnorbornenyl.

Cycloalkylalkyl comprises a noncyclic alkyl group in which a hydrogenatom which is bonded to a carbon atom, usually to a terminal C atom, hasbeen replaced by a cycloalkyl group.

Aryl refers to monocyclic or bicyclic rings having 6-12 carbon atoms,such as phenyl and naphthyl.

Arylalkyl comprises a noncyclic alkyl group in which a hydrogen atomwhich is bonded to a carbon atom, usually to a terminal C atom, has beenreplaced by an aryl group.

Heteroaryl is to be understood as meaning monocyclic or bicyclic ringswhich contain one or more, identical or different heteroatoms, such asnitrogen, sulphur or oxygen atoms, in place of one or more carbon atoms.Those which may be mentioned by way of example are furyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl,imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl,pyrimidyl, pyridazinyl, pyrazinyl and triazinyl. Examples of bicyclicheteroaryl radicals are indolyl, isoindolyl, benzofuryl, benzothienyl,benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl,cinnolinyl, phthalazinyl, quinazolinyl and benzotriazinyl, indolizinyl,oxazolopyridyl, imidazopyridyl, naphthyridinyl, indolinyl, isochromanyl,chromanyl, tetrahydroisoquinolinyl, isoindolinyl,isobenzotetrahydrofuryl, isobenzotetrahydrothienyl, isobenzothienyl,benzoxazolyl, pyridopyridyl, benzotetrahydrofuryl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl,phenothiazinyl, pteridinyl, benzo-thiazolyl, imidazopyridyl,imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzo-thiopyranyl, coumarinyl,isocoumarinyl, chromonyl, chromanonyl, pyridyl-N-oxidetetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,dihydroiso-quinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl-N-oxide,pyrimidinyl-N-oxide, pyridazinyl-N-oxide, pyrazinyl-N-oxide,quinolinyl-N-oxide, indolyl-N-oxide, indolinyl-N-oxide,isoquinolyl-N-oxide, quinazolinyl-N-oxide, quinoxalinyl-N-oxide,phthalazinyl-N-oxide, imidazolyl-N-oxide, isoxazolyl-N-oxide,oxazolyl-N-oxide, thiazolyl-N-oxide, indolizinyl-N-oxide,indazolyl-N-oxide, benzothiazolyl-N-oxide, benzimidazolyl-N-oxide,pyrrolyl-N-oxide, oxadiazolyl-N-oxide, thiadiazolyl-N-oxide,triazolyl-N-oxide, tetrazolyl-N-oxide, benzothiopyranyl-S-oxide andbenzothiopyranyl-S,S-dioxide.

Heteroarylalkyl comprises a noncyclic alkyl group in which a hydrogenatom which is bonded to a carbon atom, usually to a terminal C atom, hasbeen replaced by a heteroaryl group.

Heterocycloalkyl refers to saturated or unsaturated, nonaromaticmonocyclic, bicyclic or bridged bicyclic rings which comprise 3-12carbon atoms and which carry heteroatoms, such as nitrogen, oxygen orsulphur, in place of one or more carbon atoms. Examples of theseheterocycloalkyl radicals are tetrahydrofuryl, pyrrolidinyl, pyrrolinyl,imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl,piperazinyl, indolinyl, isoindolinyl, morpholinyl, thiomorpholinyl,homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl,thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-dioxide, tetrahydropyranyl,tetra-hydrothienyl, homothiomorpholinyl-S,S-dioxide, oxazolidinonyl,dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridyl,dihydropyrimidinyl, dihydrofuryl, dihydropyranyl,tetrahydrothienyl-S-oxide, tetrahydrothienyl-S,S-dioxide,homothiomorpholinyl-S-oxide, 2-oxa-5-azabicyclo[2.2.1 ]heptane,8-oxa-3-azabicyclo[3.2.1 ]octane, 3,8-diazabicyclo-[3.2.1 ]octane,2,5-diazabicyclo[2.2. 1]heptane, 3,8-diazabicyclo[3.2.1 ]octane,3,9-diazabicyclo[4.2.1 ]nonane and 2,6-diazabicyclo[3.2.2]nonane.

Heterocycloalkylalkyl refers to a noncyclic alkyl group in which ahydrogen atom which is bonded to a carbon atom, usually to a terminal Catom, has been replaced by a heterocycloalkyl group.

The following examples illustrate the present invention without,however, limiting its scope.

Synthesizing the Reagents

R-1) cis-1-Methylamino-4-(pyrrolidin-1-yl)cyclohexane

R-1a) tert-Butyl cis-4-(pyrrolidin-1-yl)cyclohexanecarbamate

25 mg of potassium hydrogen carbonate are added to a solution oftert-butyl cis-4-aminocyclohexanecarbamate (10 g, 46 mmol) and1,4-dibromobutane (12.1 g, 56 mmol) in 400 ml of DMF, and the mixture isstirred at RT for 24 h. The reaction mixture is then evaporated and theresidue is taken up in diethyl ether; this solution is washed withwater. The organic phase is dried and evaporated in vacuo. Yield: 12g.

R-1b) tert-Butyl N-methyl-cis-4-(pyrrolidin-1-yl)-cyclohexanecarbamate

R-1a (5 g, 18 mmol) is dissolved in 20 ml of N,N-dimethylacetamide andthis solution is added, at 37° C., to a suspension of sodium hydride(60% in liquid paraffin, 0.8 g, 20 mmol) in 20 ml ofN,N-dimethylacetamide such that the temperature does not exceed 48° C.After the foam formation has come to an end, methyl iodide (2.9 g, 20mmol) is added and the mixture is stirred at RT for 10 min. Ethylacetate is added to the reaction mixture and the whole is washed withwater. The organic phase is then treated with oxalic acid and washedwith ethyl acetate. After that, the mixture is made alkaline withpotassium hydrogen carbonate and extracted with ethyl acetate. Theorganic phases are evaporated and the residue is reacted without furtherpurification. Yield: 1.4 g.

R-1b (1.4 g, 5 mmol) is dissolved in 50 ml of dichloromethane afterwhich 25 ml of trifluoroacetic acid are added and the whole is stirredat RT for 4 h. After the reaction mixture has been evaporated, thedesired product is precipitated as the dihydrochloride usinghydrochloric acid (1 N in diethyl ether). Yield: 1 g

R-2) trans-1-Amino-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)cyclohexane

Triethylamine (21 g, 0.21 mol), benzyl trans-4-aminocyclohexylcarbamate(24.8 g, 0.1 mol) and a catalytic quantity of DMAP are addedconsecutively to a solution of 2,5-bis(p-tosyloxymethyl)tetrahydrofuran(44 g, 0.1 mol) in 440 ml of toluene. The reaction mixture is heatedunder reflux for 6 d. After cooling down, the organic phase is decantedoff from the insoluble resin and the residue is purifiedchromatographically. The intermediate which is obtained in this way issuspended in 300 ml of methanol in an autoclave, after which 37 ml ofhydrochloric acid (6 N in isopropanol) and 6 g of palladium on activecharcoal are added. The reaction mixture is stirred under a hydrogenatmosphere (50 bar) at RT for 15 h. After filtering through Celite®, thefiltrate is evaporated and the residue is taken up in hot ethyl acetate;37 ml of hydrochloric acid (6 N in isopropanol) are added to thissolution. On cooling, the desired product precipitates as thehydrochloride salt, which is filtered and dried.

R-3) 1-Amino-4-(methylpropylamino)cyclohexane

R-3a) tert-Butyl cis-4-(2,2,2-trifluoroacetylamino)cyclohexanecarbamate

A solution of tert-butyl cis-4-aminocyclohexanecarbamate (22.1 g, 103mmol) and methyl trifluoroacetate (11 ml, 110 mmol) in 110 ml ofmethanol is stirred at RT for 4 h. After the reaction mixture has beencooled down to 0° C., the precipitate is filtered off, washed withdiethyl ether and dried. Yield: 17.6 g.

R-3b) tert-Butylcis-4-methyl-(2,2,2-trifluoroacetyl)aminocyclohexanecarbamate

Sodium hydride (60% in liquid paraffin, 1.3 g, 32 mmol) is added, at RTand under a nitrogen atmosphere, to a suspension of R-3a (8.3 g, 27mmol) in 100 ml of N,N-dimethylacetamide. After 20 min, methyl iodide(4.5 g, 32 mmol) is added and the mixture is stirred at RT for 15 h.Following hydrolysis with 800 ml of ice water, the precipitate isfiltered off and washed with water and petroleum ether. The residue isrecrystallized from 200 ml of diisopropyl ether to which 10 ml ofacetonitrile have been added. Yield: 11 g.

R-3c) tert-Butyl cis-4-methylaminocyclohexanecarbamate

In order to eliminate the trifluoroacetate group, 117 ml of sodiumhydroxide solution (2 N) are added to R-3b (39.7 g, 123 mmol) in 536 mlof methanol and the mixture is stirred at RT for 5 h. The reactionmixture is evaporated and the residue is extracted by shaking with waterand ethyl acetate. The organic phase is dried, filtered and evaporatedin vacuo. Yield: 28.4 g.

R-3d) tert-Butyl cis-4-(methylpropylamino)cyclohexanecarbamate

Triethylamine (0.98 g, 9.7 mmol) and n-propyl bromide (1.2 g, 9.7 mmol)are added to a solution of R-3c (2 g, 8.8 mmol) in 5 ml of acetonitrileand the mixture is stirred at 60° C. for 3 h in a pressure tube. Thereaction mixture is then evaporated and the residue is extracted byshaking with water and ethyl acetate. Yield: 1 g. The BOC protectinggroup is eliminated, in analogy with the preparation of R-1, using R-3d(1 g, 3.7 mmol), 20 ml of trifluoroacetic acid and 20 ml ofdichloro-methane. Yield: 0.6 g

R-4) Cyclopropylpiperidin-4-ylamine

A solution of 1-tert-butoxycarbonylpiperidin-4-one (1 g, 5 mmol) andcyclopropylamine (352 μl) in 15 ml of 1,2-dichloroethane is stirred atRT for 20 min after which sodium trisacetoxyborohydride (1.6 g, 7 mmol)and 0.3 ml of acetic acid are added. After having been stirred at RT for15 h, the reaction mixture is hydrolysed with a saturated solution ofsodium hydrogen carbonate and extracted with 2×50 ml of dichloromethane.The combined organic phases are washed with a saturated solution ofsodium chloride, dried, filtered and evaporated. The residue is taken upin 4 ml of diethyl ether after which 8 ml of hydrochloric acid (4 N indioxane) are added. After stirring at RT for 15 h, the precipitate isfiltered off and washed with diethyl ether. The desired product isobtained as hydrochloride. Yield: 0.96 g

R-5) 1-Cyclopentylpiperidine-4-carboxylic acid

Catalytic quantities of p-toluenesulphonic acid (750 mg) and 12.5 ml ofglacial acetic acid are added to a solution of ethylpiperidine-4-carboxylate (22.9 g, 145 mmol) and cyclopentanone (13.5 g,160 mmol) in 400 ml of THF. After stirring at RT for 30 min, sodiumtriacetoxyborohydride (42 g, 190 mmol) is added in portions. Thereaction mixture is stirred at RT for 15 h and, after evaporating, theresidue is extracted by shaking with sodium carbonate solution anddichloro-methane. The organic phase is dried, filtered and evaporated.Yield: 32 g of ethyl 1-cyclopentylpiperidine-4-carboxylate. Theintermediate compound (1 g, 4.4 mmol) is then hydrolysed, in 10 ml ofEtOH, at 80° C. for 15 h with 10 ml of NaOH (5 N). After having beencooled down, the reaction mixture is acidified and the resultingprecipitate is filtered off.

R-6) cis-4-(Pyrrolidin-1-yl)cyclohexanecarboxylic acid

1,4-Dichlorobutane (2.3 ml, 21 mmol), potassium carbonate (12.6 g, 91mmol) and potassium iodide (400 mg) are added to a solution of methylcis-4-aminocyclo-hexanecarboxylate hydrochloride (4 g, 21 mmol) in 32 mlof DMF and the mixture is stirred at 100° C. for 6 h and then at RT for3 d. The reaction mixture is diluted with 200 ml of water, neutralizedwith glacial acetic acid, saturated with sodium chloride and extractedwith dichloromethane. The organic phases are dried, filtered andevaporated. Yield: 3.8 g of methylcis-4-(pyrrolidin-1-yl)cyclohexanecarboxylate. The intermediate is thenstirred, in 10 ml of methanol, with 25 ml of sodium hydroxide solution(1 N) at RT for 15 h. After the methanol has been removed in vacuo, thereaction mixture is adjusted to pH 6 with hydrochloric acid andevaporated further. The residue is taken up in methanol and purified byfiltration through silica gel. Yield: 3.5 g.

R-7) 3-Morpholin-4-ylcyclobutylamine

R-7a) 3-tert-Butoxycarbonylaminocyclobutyl toluene-4-sulphonate

A solution of toluene-4-sulphonyl chloride (20.5 g, 0.105 mol) in 150 mlof chloroform is added dropwise, at 0° C., to a solution of3-tert-butoxycarbonyl-aminocyclobutanol (18.7 g, 0.1 mol) andtriethylamine (12.1 g, 0.12 mol) in 500 ml of chloroform and the mixtureis then warmed to RT. The organic phase is washed consecutively withwater, dilute hydrochloric acid, sodium hydrogen carbonate solution andonce again with water before it is dried, filtered and evaporated.

R-7b) 1-Morpholin-1-yl-3-tert-butoxycarbonylamino-cyclobutane

R-7a (34 g, 0.1 mol) is dissolved in 750 ml of morpholine after which acatalytic quantity of DMAP is added and the mixture is stirred at 100°C. for 3 h under an argon atmosphere. The reaction mixture is thenevaporated in vacuo, after which the residue is coevaporated with 100 mlof toluene and then taken up in 500 ml of ethyl acetate. The organicphase is washed with a saturated solution of sodium hydrogen carbonate,dried, filtered and evaporated, with the desired compound, which is usedwithout any further purification, being obtained. 260 ml of hydrochloricacid (2 N) are added to R-7b (25.6 g, 0.1 mol) and the mixture isstirred at 40° C. for 2 h. After the reaction has been completed, thereaction mixture is made alkaline with methanolic ammonia solution,filtered and evaporated. The residue is then recrystallized fromethanol, with R-7 being obtained.

H-1) Methyl 4-hydrazino-3-methylbenzoate

50 ml of conc. hydrochloric acid are added to methyl4-amino-3-methylbenzoate (10 g, 61 mmol) and the mixture is cooled downto −15° C. A solution of sodium nitrite (6.3 g, 91 mmol) in 50 ml ofwater is added dropwise in such a way that the temperature does notexceed −5° C. After stirring at −10° C. for 4 h, a solution of tin(II)chloride dihydrate in 50 ml of conc. hydrochloric acid is added dropwiseto the suspension, with the reaction temperature not exceeding −5° C.The viscous suspension is stirred at RT for 15 h before it is adjustedto pH 14 with 200 ml of sodium hydroxide solution (10 N). The reactionmixture is filtered through kieselguhr and Extrelut® (60 g) and rinsedwith 2 l of chloroform. The organic phase which is obtained is washedwith water (2×200 ml), dried over sodium sulphate and evaporated invacuo. The residue is stirred up with 120 ml of petroleum ether andfiltered. Yield: 6.3 g

H-2) Methyl 4-hydrazino-3-fluorobenzoate

The desired compound is obtained in analogy with the preparation of H-1,starting from methyl 4-amino-3-fluorobenzoate (3.9 g, 23 mmol), sodiumnitrite (2.4 g, 34 mmol) and tin(II) chloride dihydrate (20.8 g, 92mmol). Yield: 3.4 g

H-3) 3-Iodophenylhydrazine

The desired compound is thus obtained, as hydrochloride, in analogy withthe preparation of H-1, starting from 3-iodoaniline (2.75 g, 22.8 mmol),sodium nitrite (1.58 g, 22.8 mmol) and tin(II) chloride dihydrate (15.4g, 68.5 mmol). Yield: 3.55 g

H-4) 3-Hyydrazinophenylacetic acid

The desired compound is obtained in analogy with the preparation of H-1,starting from 3-aminophenylacetic acid (2 g, 13.2 mmol), sodium nitrite(0.91 g, 13.2 mmol) and tin(II) chloride dihydrate (6.1 g, 26.4 mmol).

H-5) Piperidin-4-yl-hydrazine

4-Oxopiperidine-1-tert-butoxycarbonyl (500 mg, 2.5 mmol) is dissolved,under an argon atmosphere, in hexane, after which tert-butyl carbazate(332 mg, 2.5 mmol) is added. After 20 min of heating under reflux, thereaction mixture is cooled down and the resulting precipitate isfiltered off. Borane-THF complex (1 M in THF; 2.2 ml) is added to4-(tert-butoxycarbonylhydrazono)piperidine-1-tert-butoxycarbonyl (707mg, 2.3 mmol) and the mixture is stirred at RT for 1 h. The desiredproduct is then precipitated, as hydrochloride, with 6 ml ofhydrochloric acid (4 N in dioxane), and filtered off.

H-6) Ethyl 4-hydrazinocyclohexanecarboxylate

The desired product is obtained, as a cis/trans mixture, in analogy withthe preparation of H-5, starting from ethyl 4-oxocyclohexanecarboxylate(4.5 g, 26.4 mmol), tert-butyl carbazate (3.5 g, 26.4 mmol) andborane-THF complex (1 M in THF; 26.5 ml); the cis/trans mixture is thensubjected to further use without any additional purification orseparated chromatographically on silica gel using 0-33% ethyl acetate incyclohexane.

Yield: cis: 2.2 g

-   -   trans: 2.6 g

H-7) 2-Chloro-4-hydroxymethylphenylhydrazine

Diisobutylaluminium hydride (1M in toluene, 190 ml) is added dropwise,under a nitrogen atmosphere and at −73° C., to a solution of methyl3-chloro-4-hydrazino-benzoate (9.5 g, 47 mmol) in 1 l of toluene in sucha way that the temperature does not rise above −70° C. The reactionmixture is stirred at −73° C. for 30 min and then warmed to −5° C.Following hydrolysis with 500 ml of water, the precipitate is filteredoff and washed with ethyl acetate (5×500 ml). The organic phase isevaporated, after which the residue is taken up in a little ethylacetate and precipitated with petroleum ether/diethyl ether and filteredoff. The solid which is obtained in this way is purifiedchromatographically on silica gel using cyclo-hexane/ethyl acetate.Yield: 2.9 g

H-8) Methyl 3-hydrazinomethylbenzoate

A solution of 3 g of methyl 3-bromomethylbenzoate (13 mmol), 2.6 g oftert-butoxycarbonylhydrazine (19 mmol) and 3.1 g of potassium carbonate(23 mmol) in 30 ml of DMF is stirred at RT for 24 h. After water hasbeen added, the reaction mixture is extracted with dichloromethane. Theorganic phase is dried, filtered and evaporated, and the residue ispurified chromatographically. The BOC protecting group is theneliminated using 30 ml of hydrochloric acid (4 M in dioxane). Yield:1.25 g

H-9) (4-Trifluoromethylpyridin-3-yl)hydrazine

The desired compound is obtained in analogy with the preparation of H-1,starting from 3-amino-4-trifluoromethylpyridine (5.1 g, 31 mmol), sodiumnitrite (2.2 g, 31 mmol) and tin(II) chloride dihydrate (21.6 g, 94mmol). Yield: 3.8 g

H-10) N-(4-Hydrazinophenyl)-N-methylacetamide

The desired compound is obtained in analogy with the preparation of H-1,starting from N-(4-aminophenyl)-N-methylacetamide (0.4 g, 2.4 mmol),sodium nitrite (0.2 g, 2.7 mmol) and tin(II) chloride dihydrate (1.6 g,7.3 mmol). Yield: 0.2 g

H-11) (4-Morpholin-4-ylmethylphenyl)hydrazine

The desired compound is obtained in analogy with the preparation of H-1,starting from 4-morpholin-4-ylmethylphenylamine (1.1 g, 5 mmol), sodiumnitrite (0.3 g, 5 mmol) and tin(II) chloride dihydrate (5.8 g, 25 mmol).Yield: 0.3 g

H-12) Pyrrolidin-3-ylhydrazine

The desired compound is obtained, as the hydrochloride, in analogy withthe preparation of H-5, starting from tert-butyl3-oxopyrrolidine-1-carboxylate.

H-13) [3-(2-Methylpropane-1-sulphonyl)phenyl]hydrazine

The desired compound is obtained, as the hydrochloride, in analogy withthe preparation of H-1, starting from3-(2-methylpropane-1-sulphonyl)phenylamine (1.5 g, 7 mmol), which can beprepared in analogy with the literature (A. Courtin, Helv. Chim. Acta1981, 64, 1849), sodium nitrite (0.5 g, 7 mmol) and tin(II) chloridedihydrate (4.9 g, 21 mmol). Yield: 1.8 g

H-14) 4-Hydrazinophenylacetonitrile

The desired compound is obtained, as the hydrochloride, in analogy withthe preparation of H-1, starting from 4-aminophenylacetonitrile (5 g37.8 mmol), sodium nitrite (2.6 g, 37.4 mmol) and tin(II) chloridedihydrate (25.8 g, 112 mmol). Yield: 5.4 g

H-15) (1-Methyl-1H-indazol-5-yl)hydrazine

The desired compound is obtained, as the hydrochloride, in analogy withthe preparation of H-1, starting from 1-methyl-1H-indazol-5-ylamine (0.9g 6 mmol), sodium nitrite (0.44 g, 6.4 mmol) and tin(II) chloridedihydrate (2.8 g, 12.6 mmol). Yield: 1.2 g

Synthesizing the Intermediate Compounds

Z-1)N-[7-Oxo-6-(pyrimidine-5-carbonyl)-4,5,6,7-tetrahydrobenzothiazol-2-yl]acetamide

A solution of 10 g (48 mmol) of Z-6 in 11 of THF is cooled to −40° C.after which 143 ml (143 mmol) of Li-HMDS (1 N in THF) are added dropwisein such a way that the temperature does not exceed −20° C. After 3.5 hat −40 to −20° C., pyrimidine-5-carbonyl chloride hydrochloride (10.2 g,57 mmol) is added to the suspension and the mixture is stirred at RT for16 h. 200 ml of hydrochloric acid (1 N in Et₂O) are then added to theclear reaction mixture, in connection with which a precipitate isformed. 300 ml of phosphate buffer are added to a suspension and themixture is extracted with ethyl acetate after the organic phase has beenseparated off. The combined organic phases are dried over magnesiumsulphate and evaporated to dryness. The residue is crystallized fromacetonitrile. Yield: 13.2 g. The crude product is used for furthersyntheses without any additional purification.

Z3)N-[7-Oxo-6-(pyrazine-2-carbonyl)-4,5,6,7-tetrahydrobenzthiazol-2-yl]acetamide

10 g (48 mmol) of Z-6 are added in portions to a suspension of 8.1 g(143 mmmol) of sodium methoxide in 100 ml of DMF in such a way that thetemperature does not rise above 30° C. After it has been stirred at RTfor 1 h, the reaction mixture is heated to 55° C., at which temperaturea solution of 10 g (72 mmol) of methyl pyrazine-2-carboxylate in 40 mlof benzene is added. The solution is stirred at 55° C. for a further 3h, and then at RT for 15 h, before it is adjusted to pH 3 withhydrochloric acid (4 N in dioxane). Following hydrolysis with phosphatebuffer, the reaction mixture is extracted with ethyl acetate. Thecombined organic phases are dried and evaporated in vacuo. The residueis recrystallized from ether/petroleum ether. Yield: 8.7 g.

Z4)N-[6-(3-Nitrobenzoyl)-7-oxo-4,5,6,7-tetrahydrobenzothiazol-2-yl]acetamide

5.2 g of Z-4 are obtained, in analogy with the preparation ofintermediate compound Z-1, from 2.5 g (12 mmol) of Z-6, 4.2 g (22 mmol)of 3-nitrobenzoyl chloride and 36 ml (36 mmol) of Li-HMDS (1N in THF).The crude product is used for further syntheses without any additionalpurification.

Z5)N-[6-(4-Nitrobenzoyl)-7-oxo-4,5,6,7-tetrahydrobenzothiazol-2-yl]acetamide

2.2 g of Z-5 are obtained, in analogy with the preparation ofintermediate compound Z-1, from 1 g (4.8 mmol) of Z-6, 1.2 g (6.2 mmol)of 4-nitrobenzoyl chloride and 14.6 ml (14.6 mmol) of Li-HMDS (1 N inTHF). The crude product is used for further syntheses without anyadditional purification.

Z6) N-(7-Oxo-4,5,6,7-tetrahydrobenzothiazol-2-yl)acetamide

a) 112 g (1 mol) of 1,3-cyclohexanedione are suspended in 700 ml of icewater and 51.6 ml (1 mol) of bromine are added dropwise, at 0° C. andwithin 45 min. The suspension is subsequently stirred for 3.5 h at amax. of 10° C. The mixture is then filtered with suction and the solidis thoroughly stirred in 800 ml of water, filtered off with suction,washed with 3 l of water and dried. The solid which is obtained isrecrystallized from ethanol. Yield: 37 g (Z-6a)

b) 15.5 g (0.2 mol) of thiourea are initially introduced, at roomtemperature, in 200 ml of ethanol. 37.1 g (0.2 mol) of Z-6a are added inportions to this suspension and the mixture is then rewashed with 60 mlof ethanol. The solution, which is forming gradually, is stirred underreflux for 2 h and then evaporated. The residue is extracted with waterand diethyl ether; the water phase is made alkaline with sodiumcarbonate solution. The solid which is formed in this connection isfiltered off with suction and washed with water. It is then thoroughlystirred with methanol and this mixture is evaporated to dryness. Yield:22 g (Z-6b)

c) 230 ml (2.4 mol) of acetic anhydride are initially introduced at roomtemperature after which 22 g (0.13 mol) of Z-6b are added and themixture is stirred under reflux for 3 h. During this period, thesuspension partially goes into solution. After the mixture has beencooled down using an ice/sodium chloride bath, the solid is filtered offwith suction, boiled up 2× in in each case 150 ml of acetone, filteredoff with suction and dried. Yield: 25 g (m.p.: 268-272° C.)

Z7) N-(6-Formyl-7-oxo-4,5,6,7-tetrahydrobenzothiazol-2-yl)acetamide

20 g (0.37 mol) of sodium methoxide are suspended in 50 ml ofdimethylformamide and a suspension of 21 g (0.1 mol) of Z-6 in 100 ml ofDMF is added dropwise. The mixture is subsequently stirred for 15 minand then cooled down to 0° C. A mixture of 29.9 ml (0.37 mol) of ethylformate and 60 ml of benzene is added dropwise and the reaction mixtureis diluted with a further 100 ml of benzene. A precipitate graduallysediments and the mixture is stirred for a further 3.5 h at 0° C. Thesuspension is hydrolysed with 370 ml of 1 molar hydrochloric acid andthe solid which precipitates out in this connection is filtered off withsuction. The two phases of the mother liquor are separated and the waterphase is extracted with dichloromethane. The organic phase which resultsfrom this is dried and evaporated to dryness. The solid and the residuefrom the extraction are recrystallized from acetonitrile. Yield: 20 g

Z-8)N-[6-(Furan-2-carbonyl)-7-oxo-4,5,6,7-tetrahydrobenzothiazol-2-yl]acetamide

1.7 g of Z-8 are obtained, in analogy with the preparation of Z-7, from2 g (10 mmol) of Z-6, 1.6 g (30 mmol) of sodium methoxide and 3.8 g (30mmol) of methyl 2-furanate. (m.p.: 255-256° C.)

Z10) Methyl (2-acetylamino-7-oxo-4,5,6,7-tetrahydrobenzothiazol-6-yl)oxoacetate

52 g of Z-10 are obtained, in analogy with the preparation of Z-7, from40 g (190 mmol)of Z-6, 38 g (0.7 mmol) of sodium methoxide and 84 g (0.7mol) of dimethyl oxalate.

Z11) N-(6-Benzoyl-7-oxo-4,5,6,7-tetrahydrobenzothiazol-2-yl)acetamide

3.6 g of Z-11 are obtained, in analogy with the preparation of Z-7, from10 g (50 mmol) of intermediate compound 1, 7.8 g (140 mmol) of sodiummethoxide and 17.9 ml (140 mmol) of methyl benzoate.

Z12)N-[7-Oxo-6-(pyridine-3-carbonyl)-4,5,6,7-tetrahydrobenzothiazol-2-yl]acetamide

3.1 g of the product Z-12 are obtained, in analogy with the preparationof Z-7, from 4 g (19 mmol) of Z-6, 3.9 g (57 mmol) of sodium methoxideand 7.9 g (57 mmol) of methyl nicotinate.

Z-13) Methyl[7-oxo-6-(pyridine-3-carbonyl)-4,5,6,7-tetrahydrobenzothiazol-2-yl]carbamate

a) 2-Amino-5,6-dihydro-4H-benzothiazol-7-one

A suspension of 23 g of Z-6 (109 mmol) in a mixture of 300 ml ofhydrochloric acid (4 M in dioxane) and 30 ml of water is stirred at 60°C. for 15 h. After it has been cooled down to 0° C., the reactionmixture is made alkaline (pH 10) with 8 N sodium hydroxide solution. Theprecipitate is filtered off, washed with diethyl ether and subjected tofurther use without any additional purification. Yield: 22.4 g

b) Methyl (7-oxo-4,5,6,7-tetrahydrobenzothiazol-2-yl)carbamate

572 μl of methyl chloroformate (7.3 mmol) are added to a solution of 500mg of 2-amino-5,6-dihydro-4H-benzothiazol-7-one (2.4 mmol) in 5 ml ofpyridine. The reaction mixture is stirred at 50° C. for 15 h and thendiluted with ethyl acetate; the mixture is then extracted by shaking, ineach case 2×, with water and cold 1 N hydrochloric acid. The organicphase is dried and evaporated. Yield: 290 mg

c) The desired compound is obtained, in analogy with the preparation ofZ-1, from 340 mg of methyl(7-oxo-4,5,6,7-tetrahydrobenzothiazol-2-yl)carbamate (1.5 mmol), 4.7 mlof Li-HMDS (IN in THF) and 520 mg of imidazol-1-ylpyridin-3-ylmethanone(3 mmol) in 30 ml of THF. Yield: 480 mg

Z14) Ethyl[7-oxo-6-(pyridin-3-carbonyl)-4,5,6,7-tetrahydrobenzothiazol-2-yl]thiocarbamate

a) Ethyl (7-oxo-4,5,6,7-tetrahydrobenzothiazol-2-yl)thiocarbamate

The desired thiocarbamate is obtained in analogy with the preparation ofZ-13 b, starting from 101 g of 2-amino-5,6-dihydro-4H-benzothiazol-7-one(602 mmol) in 3.41 of pyridine and 75 g of ethyl chlorothioformate (602mmol). Yield: 84 g

b) The desired compound is obtained, in analogy with the preparation ofZ-1, from 17 g of ethyl(7-oxo-4,5,6,7-tetrahydrobenzothiazol-2-yl)thiocarbamate (67 mmol), 200ml of Li-HMDS (1N in THF) and 23 g of imidazol-1-ylpyridin-3-ylmethanone(133 mmol) in 400 ml of THF. Yield: 18 g

Z-15) Ethyl[7-oxo-6-(pyrimidine-5-carbonyl)-4,5,6,7-tetrahydrobenzothiazol-2-yl]thiocarbamate

The desired compound is obtained, in analogy with the preparation ofZ-1, from 12 g of ethyl(7-oxo-4,5,6,7-tetrahydrobenzothiazol-2-yl)thiocarbamate (Z-14a, 46mmol), 140 ml of Li-HMDS (1N in THF) and 12 g ofimidazol-1-ylpyrimidin-5-ylmethanone (56 mmol) in 300 ml of THF. Yield:13 g

I-1)4-(7-Acetylamino-4,5-dihydropyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-1-yl)-3-chlorobenzoicacid

A suspension of Z-13 (480 mg, 1.5 mmol) and 2-chlorophenylhydrazinehydrochloride (267 mg, 1.5 mmol) in 10 ml of glacial acetic acid isstirred at 100° C. for 4 h. The reaction mixture is then diluted with500 ml of water and the precipitate is filtered off. Yield: 116 mg

I-3)N-[1-(2-Chloropyridin-4-yl)-3-furan-2-yl-4,5-dihydro-1H-pyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-7-yl]acetamide

The desired product is obtained in analogy with the preparation of I-1,starting from Z-8 (1.5 g, 5 mmol) and 2-chloropyridin-4-ylhydrazinehydrochloride in 25 ml of glacial acetic acid. Yield: 1.6 g

I4)4-(7-Acetylamino-3-furan-2-yl-4,5-dihydro-pyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-1-yl)-3-chlorobenzoicacid

In analogy with the preparation of I-1, Z-8 (12 g, 35 mmol) and methyl3-chloro-4-hydrazinobenzoate (8.5 g, 35 mmol) are stirred in 80 ml ofglacial acetic acid at RT for 4 d. The methyl ester (1.1 g) which isobtained after precipitating in ice water is then hydrolysed usinglithium hydroxide (178 mg in 15 ml of dioxane). Acidifying with 2 Nhydrochloric acid yields the desired product as a solid. Yield: 0.8 g

I-6)7-Acetylamino-1-phenyl-4,5-dihydro-1H-pyrazolo[3′,4′:3,4]benzo[1,2-d]thiazole-3-carboxylicacid

27 g of product are obtained in analogy to the preparation of I-1 from30 g (0.1 mol) of Z-10 and 10.3 ml (0.1 mol) of phenyl hydrazine. (m.p.:298-300° C.). 0.1 g of this compound (0.3 mmol) is suspended in 12 ml ofmethanol/water (1:1) after which 0.4 ml of a 10% potassium hydroxidesolution is added. After 1.5 h, the reaction mixture is evaporated andthe solution is acidified with dilute hydrochloric acid. The resultingprecipitate is recrystallized from acetonitrile. Yield: 0.1 g(m.p.: >300° C.)

I-8)4-(7-Acetylamino-3-phenyl-4,5-dihydropyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-1-yl)-3-chlorobenzonitrile

The desired product is obtained in analogy with the preparation of I-1,starting from Z-11 (10 g; 12.7 mmol) and3-chloro-4-hydrazinobenzonitrile (4.5 g, 26.8 mmol) in 50 ml of glacialacetic acid. Yield: 1.6 g

I-9) 4-(7-Acetylamino-3-phenyl-4,5-dihydropyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-1-yl)-3-chlorbenzoic acid

The desired compound is obtained in analogy with the preparation of I-4,starting from Z-11 (2.3 g, 7.1 mmol) and methyl3-chloro-4-hydrazinobenzoate (1.8 g, 8.5 mmol). Yield: 0.36 g

I-10)N-[1-(2-Chloro-4-nitrophenyl)-3-phenyl-4,5-dihydro-1H-pyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-7-yl]acetamide

The desired product is obtained in analogy with the preparation of I-1,starting from Z-11(7.5 g; 13.1 mmol) and3-chloro-4-hydrazinonitrobenzene (3.2 g, 14.4 mmol) in 100 ml of glacialacetic acid. Yield: 1.1 g

I-11)N-(1-Piperidin-4-yl-3-pyridin-3-yl-4,5-dihydro-1H-pyrazolo-[3′,4′:3,4]benzo[1,2-d]thiazol-7-yl)acetamide

In analogy with the preparation of I-1, Z-12 (2.5 g, 7.9 mmol) and H-5(1.2 g, 7.9 mmol) are stirred in 50 ml of glacial acetic acid at 60° C.for 15 h. The mixture is poured onto ice water and rendered alkalinewith 1 N sodium hydroxide solution (pH 12). The resulting precipitate isfiltered off, washed with water and dried at 40° C. in vacuo. Yield: 2 g

I-12)4-(7-Acetylamino-3-pyridin-3-yl-4,5-dihydropyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-1-yl)cyclohexanecarboxylicacid

The desired compound is obtained in analogy with the preparation of I-4starting from Z-12 (1.9 g, 5.8 mmol) and H-6 (1.3 g, 5.8 mmol). Yield:0.78 g.

The corresponding cis and trans compounds are obtained by using theisomerically pure cisH-6 and transH-6, respectively.

Other intermediate compounds which are prepared in analogy with theabove-described syntheses. Starting No. compound Structure I-13 Z-12

I-14 Z-12

I-15 Z-12

I-16 Z-12

I-17 Z-12

I-18 Z-12

I-19 Z-12

I-20 Z-12

I-21 Z-12

I-22 Z-12

I-23 Z-12 H-2

I-24 Z-12 H-3

I-25 Z-12

I-26 Z-12 H-4

I-27 Z-1

I-28 Z-3 H-1

I-29 Z-3 H-7

I-30 Z-3

I-31 Z-3

I-32 Z-4

I-33 Z-4

I-34 Z-5

I-35 Z-5

I-36 Z-12

I-37 Z-11

I-38 Z-11

I-39 Z-12

I-40 Z-12 H-12

I-41 Z-14

I-42 Z-14

I-43 Z-14

I-44 Z-15

I-45 Z-3

I-45 Z-12

II-1)N-[1-(4-Amino-2-chlorophenyl)-3-furan-2-yl-4,5-dihydro-1H-pyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-7-yl]acetamide

Diphenyl phosphoryl azide (1.1 ml, 5 mmol) and 0.7 ml of triethylamineare added to a solution of I-4 (2.1 g, 4.6 mmol) in 20 ml of DMF and themixture is stirred at 50° C. for 6 h. p-Toluenesulphonic acid (1.5 g,9.1 mmol) and 3 ml of water are added to the reaction mixture, which isstirred at 50° C. for 39 h. The mixture is then poured onto 300 ml ofice water and the resulting precipitate is filtered off. The residue ispurified chromatographically on silica gel usingdichloromethane:methanol:ammonia 98:2:0.2. Yield: 0.6 g

II-3)N-[1-(4-Amino-2-chlorophenyl)-3-phenyl-4,5-dihydro-1H-pyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-7-yl]acetamide

Iron powder (0.77 g, 13.8 mmol) is added to a solution of I-10 (1.1 g, 2mmol) in 20 ml of glacial acetic acid and the mixture is stirred at 70°C. for 4 h. After filtering through kieselguhr, the solvent is removedin vacuo and the residue is purified chromatographically on silica gelusing dichloromethane:methanol 99:1. Yield: 0.8 g

II-4)N-[1-(4-Aminophenyl)-3-pyridin-3-yl-4,5-dihydro-1H-pyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-7-yl]acetamide

The desired product is obtained in analogy with the preparation of II-2,starting from I-16 (0.2 g, 0.5 mmol). Yield: 0.14 g

II-5)N-[1-(3-Aminophenyl)-3-pyridin-3-yl-4,5-dihydro-1H-pyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-7-yl]acetamide

I-17 (1.2 g, 2.8 mmol) is suspended in 150ml of methanol in a 250 mlhydrogenation reactor. Palladium (5% on active charcoal, 120 mg) isadded to the suspension and the latter is stirred at RT and a hydrogenpressure of 50 psi. In each case the same quantity of catalyst is addedonce again after 18 h and after 40 h. After a further 15 h, the catalystis filtered off and the solvent is removed in vacuo. Yield: 0.89 g

II-6)N-[1-(4-Amino-2-chlorophenyl)-3-pyridin-3-yl-4,5-dihydro-1H-pyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-7-yl]acetamide

The desired product is obtained in analogy with the preparation of II-3,starting from I-18 (10 g, 21 mmol). Yield: 8.4 g

II-9) Ethyl[4-(7-acetylamino-3-phenyl-4,5-dihydropyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-1-yl)-3-chlorophenyl]thiocarbamate

Ethyl chlorothioformate (0.7 ml) is added dropwise to a solution of II-6(3 g, 5.8 mmol) in 75 ml of pyridine and the mixture is stirred at RTfor 4 h. After the pyridine has been removed on a rotary evaporator, theresidue is taken up in water and the precipitate is filtered off. Asolid, which is dried in vacuo at 60° C. for 15 h, is obtained. Yield: 3g

II-10)N-[1-(4-Aminomethyl-2-chlorophenyl)-3-phenyl-4,5-dihydro-1H-pyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-7-yl]acetamide

20 mg of Raney nickel are added to a solution of I-8 (1.5 g, 3.3 mmol)in 150 ml of ammoniacal methanol and the mixture is stirred at RT for 15h under a hydrogen atmosphere (3.5 bar). The mixture is taken up indichloromethane and this solution is filtered through silica gel. Afterthe solvent has been removed in vacuo, the residue is crystallized fromdiethyl ether/petroleum ether. Yield: 1.1 g

II-11)N-[1-(2-Chloro-4-formylphenyl)-3-pyrazin-2-yl-4,5-dihydro-1H-pyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-7-yl]acetamide

2 g of manganese dioxide are added to a solution of I-29 (0.5 g, 1.1mmol) in 25 ml of acetone and the mixture is refluxed for 3 h. Thereaction mixture is then filtered and the solvent is removed in vacuo.Yield: 0.25 g

II-12)N-[1-(3-Aminomethyl)-3-phenyl-4,5-dihydro-1H-pyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-7-yl]acetamide

The desired product is obtained in analogy with the preparation ofII-10, starting from I-38 (2.3 g, 5.6 mmol). Yield: 1.4 g

II-13)N-[1-(4-Amino-2-fluorophenyl)-3-pyridin-3-yl-4,5-dihydro-1H-pyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-7-yl]acetamide

The desired product is obtained in analogy with the preparation of II-3,starting from I-39 (1 g, 2.2 mmol). Yield: 1 g

II-14)4-(7-Amino-3-pyridin-3-yl-4,5-dihydropyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-1-yl)-N,N-dimethylbenzamide

10 ml of conc. hydrochloric acid and 100 ml of water are added to asolution of I-20 (6.3 g, 14.5 mmol) in 150 ml of dioxane and the mixtureis heated under reflux for 6 h. The clear solution is stirred at 50° C.for a further 16 h and then evaporated to dryness in vacuo. Thedeacetylation product (6.6 g, 14 mmol) is dissolved in 150 ml of DMFafter which TBTU (5.1 g, 15 mmol) and 10 ml of triethylamine are added.The reation mixture is stirred at RT for 30 min, after whichdimethylamine hydrochloride (1.25 g, 15 mmol) is added and the mixtureis stirred at RT for a further 6 h. Following hydrolysis with 1 l ofwater, the resulting precipitate is filtered off and dried in vacuo.Yield: 5.5 g

II-15)4-(7-Amino-3-pyridin-3-yl-4,5-dihydropyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-1-yl)-3-chloro-N,N-dimethylbenzamidedihydrochloride

5.5 ml of hydrochloric acid (4 M in dioxane) and 5.5 ml of water areadded to a solution of Example 2.180 (500 mg, 1 mmol) and the mixture isheated at 80° C. for 2.5 h. The clear solution is stirred at 70° C. fora further 15 h and then evaporated to dryness in vacuo. Yield: 580 mg

II-16)4-(7-Amino-3-pyridin-3-yl-4,5-dihydropyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-1-yl)-3-fluoro-N,N-dimethylbenzamide

30 ml of hydrochloric acid (37%) and 35 ml of water are added to asolution of Example 2.182 (1.37 g, 2.9 mmol) and the mixture is heatedat 50° C. for 12 h. After evaporating in vacuo, the residue is taken upin water and 4 N sodium hydroxide solution is added. The resultingprecipitate is filtered and dried. Yield: 1.1 g

II-17)1-(2-Chlorophenyl)-3-pyridin-3-yl-4,5-dihydro-1H-pyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-7-ylamine

The desired product is obtained in analogy with the preparation ofII-16, starting from I-46 (10.3 g, 24 mmol) and 280 ml of hydrochloricacid (37%) in 330 ml of water. Yield: 7.6 g

II-18)1-Phenyl-3-pyridin-3-yl-4,5-dihydro-1H-pyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-7-ylamine

The desired product is obtained in analogy with the preparation ofII-16, starting from Example 1.13 (7.7 g, 20 mmol), and 50 ml ofhydrochloric acid (37%) in 30 ml of water. Yield: 6.8 g

II-19)4-(7-Amino-3-pyridin-3-yl-4,5-dihydropyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-1-yl)-3-chlorobenzoicacid

The desired product is obtained in analogy with the preparation ofintermediate compound II-16, starting from Example 1.21 (2.9 g, 5 mmol)and 2 ml of hydrochloric acid (32%) in a mixture of 10 ml of water and20 ml of dioxane. Yield: 2.7 g

Analytical Methods

Method AM1: HPLC: Agilent 1100 series; MS: 1100 series LC/MSD (API-ES(+/−3000 V, Quadrupole, G1946D); mode: Scan pos 100-1000, neg 100-1000Column: Waters; part no. 186000594; XTerra MS C18 2.5 μm; 2.1 × 50 mmcolumn Solvent: A: H₂O, deionized and containing 0.1% added formic acidB: Acetonitrile, HPLC grade and contaiing 0.1% added formic acidDetection: peak width > 0.1 min (2 s); 190-450 nm UV 254 nm (bandwidth8, reference off) UV 230 nm (bandwidth 8, reference off) Injection: 1 μlstandard injection Flow rate: 0.6 ml/min Column temperature: 35° C. Pumpgradient: 0.0-0.5 min 5% B 0.5-1.5 min 5% -> 50% B 1.5-4.0 min 50% ->95% B 4.0-6.0 min 95% B 6.0-6.5 min 95% -> 5% B 1.5 min post run 5% B

Method AM2 HPLC: Agilent Series 1100 (G1379A/G1310A converted toG1311A/G1313A/G1316A/G1948D/G1315B/ G1946D) mode: Scan pos 100-1000, neg100-1000 Column: Agilent Zorbax SB-C8, 2.1 × 50 mm, 3.5 μm Solvent: A:H₂O, deionized and containing 0.1% added formic acid B: AcetonitrileHPLC grade and containing 0.1% added formic acid Detection: peak width >0.1 min (2 s); 190-450 nm UV 254 nm (bandwidth 8, reference off) UV 230nm (bandwidth 8, reference off) Injection: 2.5 μl standard injectionFlow rate: 0.6 ml/min Column temperature: 35° C. Pump gradient: 0-3.0min 10% -> 90% B 3.0-4.0 min 90% B 4.0-5.0 min 90% -> 10% B

Method AM3 HPLC: Agilent Series 1100 (G1312A/G1315A/G1316A/ G1367A)Agilent MSD SL ESI Mode: Scan pos 150-750 Column: Agilent Zorbax SB-C8,2.1 × 50 mm, 3.5 μm Solvent: A: H₂O deionized and containing 0.1% addedformic acid B: Acetonitrile, HPLC grade and containing 0.1% added formicacid Detection: peak width > 0.01 min (0.2 s); 190-450 nm UV 254 nm(bandwidth 16, reference off) UV 230 nm (bandwidth 8, reference off) UV214 nm (bandwidth 8, reference off) Injection: 3.0 μl overlap injectionFlow rate: 1.1 ml/min Column temperature: 45° C. Pump gradient: 0-1.75min 15% -> 95% B 1.75-1.90 min 95% B 1.90-1.92 min 950% -> 15% B

Method AM4 HPLC: Agilent 1100 series MS: Agilent LC/MSD SL (LCMS1: 1100series LC/MSD) Column: Waters, Xterra MS C18, 2.5 μm, 2.1 × 30 mm, partno. 186000592 Solvent A: H₂O deionized and containing 0.1% added formicacid B: Acetonitrile, HPLC grade and containing 0.1% added formic acidDetection: MS: positive and negative mass range: 120-900 m/z fragmentor:120 gain EMV: 1 threshold: 150 step size: 0.25 UV: 254 nm bandwidth: 1(LCMS1: 2) reference: off spectrum: range: 250-400 nm range step: 1.00nm threshold: 4.00 mAU peak width: <0.01 min (LCMS1: >0.05 min) slit: 1nm (LCMS1: 2 nm) Injection: 5 μl Flow rate: 1.10 ml/min Columntemperture: 40° C. Gradient: 0.00 min 5% B 0.00-2.50 min 5% -> 95% B2.50-2.80 min 95% B 2.81-3.10 min 95% -> 5% B

Method AM5 HPLC: Agilent 1100 series MS: Agilent LC/MSD SL (LCMS1: 1100series LC/MSD) Column: Phenomenex, Synergy Polar RP 80A, 4 μm, 2.0 × 30mm, part no. 00A-4336-B0 Solvent: A: H₂O (Millipore purified purestwater) containing 0.1% HCOOH B: Acetonitrile (HPLC grade) Detection: MS:positive and negative mass range: 120-900 m/z fragmentor: 120 Gain EMV:1 Threshold: 150 Step size: 0.25 UV: 254 nm Bandwidth: 1 (LCMS1: 2)Reference: off Spectrum: range: 250-400 nm range step: 1.00 nmthreshold: 4.00 mAU peak width: <0.01 min (LCMS1: >0.05 min) slit: 1 nm(LCMS1: 2 nm) Injection: inj. vol.: 5 μl Inj. mode: needle washSeparation: flow rate: 1.10 ml/min column temp.: 40° C. gradient: 0.00min 5% solvent B 0.00-2.50 min 5% -> 95% solvent B 2.50-2.80 min 95%solvent B 2.81-3.10 min 95% -> 5% solvent B

Method AM6 HPLC: Waters Alliance 2695 Column: Waters, Xterra MS C18, 2.5μm, 4.6 × 30 mm, part no. 186000600 Solvent A: H₂O, deionized andcontaining 0.1% added formic acid B: Acetonitrile, HPLC grade andcontaining 0.08% added formic acid Flow rate: 1 ml/min Columntemperature: 25° C. Gradient: 0.00 min 5% B 0.00-3.10 min 5% -> 98% B3.10-4.50 min 98% B 4.50-5.00 min 98% -> 5% B

Abbreviations employed conc. concentrated d day DCM dichloromethane DMAPN,N-dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethylsulphoxide EtOH ethanol h hour HATUO-(7-Azabenzotriazol-1-yl)-N,N,N′,N′- tetramethyluroniumhexafluorophosphate HPLC high performance liquid chromatography Li-HMDSlithium hexamethyldisilazane M molar MeOH methanol min minute mlmillilitre m.p. melting point MS mass spectrometry N normal NMR nuclearmagnetic resonance spectroscopy ppm parts per million Rf retentionfactor RP reversed phase RT room temperature Rt retention time TBTUO-Benzotriazol-1-yl-N,N,N′,N′- tetramethyluronium tetrafluoroborate terttertiary THF tetrahydrofuran TLC thin layer chromatography

EXAMPLES 1.1-1.13

Examples 1.1-1.13 are prepared in analogy with the I-1 synthesis.Starting Mass HPLC No. compound Structure [M + 1]⁺ Rt [min] 1.1 Z-12

394 1.88 1.2 Z-12

380 1.67 1.3 Z-8 H-8

449 2.1 1.4 Z-12 H-9

457 1.54 + 1.71 1.5 Z-12 H-10

459 1.45 1.6 Z-12 H-11

487 2.53 1.7 Z-1

403 1.88 1.8 Z-1

423 1.82 1.9 Z-12

430 1.53 1.10 Z-12 H-13

508 1.67 1.11 Z-12 H-14

427 1.49 1.12 Z-12 H-15

442 1.48 1.13

445 1.19

EXAMPLES 2 Reacting the Carboxylic Acids with Amines

Synthesis Method A

TBTU (0.15 mmol) and triethylamine (0.65 mmol) are added to a solutionof the carboxylic acid (0.1 mmol) in 5 ml of dichloromethane and themixture is stirred at RT for 15 min. The appropriate amine (0.1 mmol) isthen added and the mixture is stirred at RT until the conversion iscomplete. The reaction mixture is treated with an aqueous 5% solution ofpotassium carbonate and extracted with dichloromethane. The combinedorganic phases are dried and evaporated in vacuo. The residue iscrystallized from petroleum ether or purified chromatographically.

Synthesis Method B

HATU (0.55 mmol) and diisopropylethylamine (1.8 mmol) are added to asolution of the carboxylic acid (0.35 mmol) in 5 ml of DMF (ordichloromethane or THF) and the mixture is stirred at RT for 15 min.After the appropriate amine (0.39 mmol) has been added, the mixture isstirred at RT for 15 h, after which it is treated with aqueous 5%potassium carbonate solution and extracted with dichloromethane. Thecombined organic phases are dried and evaporated in vacuo. The residueis purified chromatographically.

Synthesis Method C

The synthesis is carried out in analogy with synthesis method B butusing triethylamine instead of diisopropylethylamine.

Synthesis Method D

The carboxylic acid is first of all immobilized on a polymer. For this,12 ml of dichloromethane are added to 1.2 g of PL-TFP resin (1.25mmol/g, 150-300 μm; Polymer Laboratories), with the appropriatecarboxylic acid (1.2 mmol in 6 ml of DMF), DMAP (0.7 mmol in 6 ml ofdichloromethane) and 0.8 ml of diisopropylcarbodiimide then beingpipetted in consecutively 5 minutes later. The mixture is left to standat RT for 36 h. The resin is filtered off through a glass frit (porosity4) and washed 4× with in each case 15 ml of DMF, 4× with in each case 20ml of dichloromethane and 4× with in each case 20 ml of THF, with thesolvent in each case dripping through the glass flit without anyvacuum/pressure and with the frit being sucked dry before each newapplication of solvent. The washed resin is dried at RT and 0.2 mbar for2 d. Yield of dry resin: 2.204 g.

For the reaction of the immobilized carboxylic acid, 110 mg (0.15 mmol)of the resin which has been prepared in this way are initiallyintroduced in 1 ml of dichloromethane and 0.5 ml of DMF after which theamine (0.1 mmol) and diisopropylethylamine (0.1 mmol) are added. Themixture is then stirred slowly at RT for 15 h. After the reaction hascome to an end, the resin is filtered off as described above and washedwith 8×3 ml of dichloromethane. The filtrate is evaporated in vacuo andthe residue is purified by means of RP-HPLC.

EXAMPLES 2.1-2.183

HPLC Rt [min] Starting Mass or m.p. # compound Structure [M + 1]⁺ orTLC:R_(f) 2.1 I-9

534 2.06 2.5 I-9

478 m.p.: 206° C. 2.6 I-9

540 R_(f) = 0.5 DCM:MeOH 9:1 2.7 I-9

546 1.94 2.8 I-9

536 2.1 2.9 I-9

534 1.88 2.10 I-9

536 2.02 2.11 I-21

576 2.06 2.12 I-21

616 1.4 2.13 I-21

465 1.42 2.14 I-21

479 2.18 2.15 I-21

570 2.02 2.16 I-21

630 1.39 2.17 I-21

630 1.28 2.18* I-21

520 1.98 2.19 I-21

616 1.32 2.20 I-21

547 1.89 2.21 I-21

541 1.86 2.22 I-21

537 1.54 2.23 I-21

563 3.2 2.24 I-21

523 1.58 2.25 I-21

547 1.5 2.26 I-21

563 1.6 2.27 I-21

549 1.45 2.28 I-21

563 1.55 2.29 I-21

549 1.53 2.30 I-21

535 1.58 2.31 I-21

537 1.58 2.32 I-21

523 1.47 2.33 I-21

537 1.58 2.34 I-21

509 1.5 2.35 I-21

549 1.55 2.36 I-21

549 1.59 2.37 I-21

632 0.55 2.38 I-21

563 1.53 2.39 I-21

658 0.52 2.40 I-21

548 2.53 2.41 I-21

533 1.76 2.42 I-21

576 2.57 2.43 I-21

576 2.56 2.44 I-21

519 1.62 2.45 I-21

660 1.39 2.46 I-21

707 1.5 2.47 I-21

709 2.75 2.48 I-21

590 2.69 2.49 I-21

630 2.77 2.50 I-21

645 2.56 2.51 I-20

528 2 2.52 I-20

596 2.11 2.53 I-20

542 2.06 2.54 I-20

582 2.1 2.55 I-20

604 1.26 2.56 I-20

584 1.33 2.57 I-20

547 1.88 2.58 I-20

535 1.84 2.59 I-20

556 1.5 2.60 I-20

551 1.83 2.61 I-22

459 1.43 2.62 I-23

521 1.54 2.63 I-23

519 1.49 2.64 I-23

477 1.43 2.65 I-23

491 1.59 2.66 I-23

535 1.63 2.67 I-23

533 1.54 2.68 I-25

521 1.75 2.69 I-25

568 0.19 2.70 I-25

556 Rf: 0.14 DCM:MeOH 7:3 2.71 I-25

529 1.5 2.72 I-25

556 R_(f) = 0.18 DCM:MeOH 7:3 2.73 I-25

612 R_(f) = 0.27 DCM:MeOH 8:2 2.74 I-25

535 1.81 2.75 I-25

517 1.53 2.76 I-25

499 1.6 2.77 I-25

485 1.48 2.78 I-25

528 2.8 2.79 I-25

517 1.51 2.80 I-25 EtOH

474 3.38 2.81 I-26

501 1.64 2.82 I-27

494 1.74 2.83 I-28

474 m.p.: 283° C. 2.84 I-45

494 1.81 2.85 I-12

519 1.77 2.86 I-12

507 1.47 2.87 I-12

465 1.39 2.88 I-36

612 1.35 2.89 I-36

626 1.33 2.90 I-36

612 1.38 2.91 I-36

626 1.36 2.92 I-36

626 1.37 2.93 I-37

478 2.00 2.94 I-37

615 1.67 2.95 I-37

561 1.60 2.96 I-37

615 1.65 2.97 I-37

547 1.60 2.98 I-37

535 1.60 2.99 I-9

615 m.p.: 280° C. 2.100 I-9

629 m.p.: 286° C. 2.101 I-12

548 1.45 2.102 I-12

522 1.46 2.103 trans-I-12

548 1.43 2.104 trans-I-12

548 1.43 2.105 trans-I-12

548 1.46 2.106 trans-I-12

520 1.37 2.107 trans-I-12

548 1.45 2.108 trans-I-12

574 1.54 2.109 I-23

505 1.6 2.110 I-23

507 1.41 2.111 I-23

546 1.52 2.112 I-23

560 1.24 2.113 I-23

560 1.48 2.115 I-23

520 1.45 2.116 I-23

548 1.49 2.117 I-23

534 1.48 2.118 I-23

560 1.53 2.119 I-23

505 1.6 2.120 I-23

586 1.61 2.121 I-23

588 1.64 2.122 I-23

574 1.27 2.123 I-23

603 1.49 2.124 I-23

588 1.28 2.125 I-23

532 1.65 2.126 I-25

517 R_(f) = 0.44 DCM: MEOH 9:1 2.127 I-25

568 R_(f) = 0.18 DCM: MEOH 7:3 2.128 I-25

582 R_(f) = 0.24 DCM: MEOH 7:3 2.129 I-25

598 1.23 2.130 I-25

527 1.39 2.131 I-25

522 1.43 2.132 I-25

522 R_(f) = 0.91 DCM: MEOH 9:1 2.133 I-25

522 R_(f) = 0.88 DCM: MEOH 9:1 2.134 I-25

591 R_(f) = 0.42 DCM: MEOH 9:1 2.135 I-25

530 R_(f) = 0.4 DCM: MEOH 9:1 2.136 I-25

544 R_(f) = 0.25 DCM: MEOH 9:1 2.137 I-25

556 1.27 2.138 I-25

459 R_(f) = 0.34 DCM: MEOH 9:1 2.139 I-25

570 R_(f) = 0.18 DCM: MEOH 8:2 2.140 I-25

570 1.43 2.141 I-20

578 1.56 2.142 I-20

591 1.53 2.143 I-20

584 1.53 2.144 I-20

568 1.61 2.145 I-20

582 1.64 2.146 I-20

556 1.50 2.147 I-20

540 1.48 2.148 I-20

590 1.65 2.149 I-20

568 1.58 2.150 I-20

528 1.44 2.151 I-20

568 1.54 2.152 I-20

556 1.29 2.153 I-20

556 1.55 2.154 I-21

536 1.48 2.155 I-21

550 1.49 2.156 I-21

562 1.49 2.157 I-21

618 1.58 2.158 I-21

630 1.50 2.159 I-21

625 1.55 2.160 I-21

602 1.65 2.161 I-21

562 1.47 2.162 I-21

616 1.72 2.163 I-21

590 1.25 2.164 I-21

574 1.55 2.165 I-21

612 1.64 2.166 I-21

625 1.58 2.167 I-21

560 1.46 2.168 I-21

562 1.77 2.169 I-21

602 1.62 2.170 I-21

590 1.62 2.171 I-21

590 1.61 2.172 I-21

604 1.68 2.173 I-21

685 2.59 2.174 I-20

542 2.56 2.176 I-41

505 2.177 I-42

676 2.178 I-42

539 2.179 I-12

465 1.46 2.180 I-21

493 1.56 2.181 I-20

459 1.5 2.182 I-23

477 2.87 2.183 II-19

477 1.44*In Example 2.18, the carboxylic acid is reacted with tert-butyl(2-aminocyclopropyl)carbamate. In the 2nd step, the BOC protecting groupis eliminated with trifluoroacetic acid.

EXAMPLES 3 Reacting the Amines which have been Prepared

Synthesis Method E—Reacting with Sulphonyl Chlorides

0.5 mmol of sulphonyl chloride is added to a solution of 0.2 mmol ofamine in 3 ml of pyridine and the mixture is stirred at RT for 15 h. Thereaction mixture is evaporated and the residue is purifiedchromatographically.

Synthesis Method F—Reacting with Carboxylic Acids

HATU (0.55 mmol) and diisopropylethylamine (1.8 mmol) are added to asolution of the carboxylic acid (0.16 mmol) in 1.3 ml of DMF and themixture is stirred at RT for 1 h. After a solution of 0.1 mmol of theappropriate amine in DMF has been added, the mixture is stirred at RTfor a further 15 h. The reaction mixture is then filtered and evaporatedand the residue is purified chromatographically.

Synthesis Method G—Reacting with Carbonyl Chlorides

0.5 mmol of carbonyl chloride is added to a solution of 0.2 mmol ofamine in 3 ml of pyridine and the mixture is stirred at RT for 15. Thereaction mixture is evaporated and the residue is purifiedchromatographically.

EXAMPLES 3.2-3.82

HPLC Rt [min] Starting Mass or m.p. # compound Structure [M + 1]⁺ orTLC:R_(f) 3.2 II-1

601 2.08 3.3 II-3

543 2.2  3.4 II-1

585 2.12 3.10 II-4

544 1.62 3.11 II-4

445 1.45 3.12 II-4

473 1.6  3.13 II-4

475 1.48 3.14 II-4

489 1.5  3.15 II-4

529 1.53 3.16 II-4

515 1.52 3.17 II-4

519 1.58 3.18 II-4

529 1.59 3.19 II-4

503 1.43 3.20 II-4

471 1.6  3.21 II-4

515 1.57 3.22 II-4

488 0.47 3.23 II-5

537 1.89 3.24 II-5

535 1.81 3.25 II-6

515 1.54 3.26 II-6

479 1.52 3.27 II-6

541 1.82 3.28 II-6

547 1.90 3.29 II-6

577 1.81 3.30 II-6

616 1.38 3.31 II-6

616 Rf: 0.18 MeOH:NH₄OH 92.5:7.5:1 3.32 II-6

509 1.43 3.33 II-6

553 1.55 3.34 II-12

569 m.p.: 277° C. 3.35 II-12

569 2.59 3.36 II-12

520 m.p.: 282° C. 3.37 II-12

617 m.p.: 227° C. 3.38 II-12

631 m.p.: 294° C. 3.39 II-12

597 3.0  3.40 II-12

605 2.95 3.41 I-11

437 1.28 3.42 I-11

451 1.4  3.43 I-11

499 1.56 3.44 I-11

500 1.21 3.45 I-11

473 1.38 3.46 I-11

499 1.68 3.47 I-11

536 1.52 3.49 I-40

522 1.47 3.50 I-11

536 1.52 3.51 I-11

465 1.47 3.52 I-11

500 1.34 3.53 I-11

500 1.46 3.54 II-13

506 1.47 3.55 II-13

463 1.46 3.56 II-4

502 1.45 3.57 II-4

502 1.45 3.58 II-14

531 1.48 3.59 II-14

545 1.56 3.60 II-14

551 1.77 3.61 II-14

541 1.67 3.62 II-14

517 1.46 3.63 II-14

519 1.57 3.64 II-14

489 1.45 3.65 II-15

547 1.74 3.66 II-16

521 1.46 3.67 II-16

567 1.77 3.68 II-17

436 1.64 3.69 II-17

450 1.75 3.70 II-17

464 1.87 3.71 II-17

452 1.59 3.72 II-17

498 1.88 3.73 II-17

512 1.95 3.74 II-17

506 1.68 3.75 II-17

507 1.57 3.76 II-17

494 1.64 3.77 II-17

478 1.58 3.78 II-17

493 1.28 3.79 II-17

466 1.61 3.80 II-18

418 1.54 3.81 II-18

431 1.53 3.82 II-18

473 1.55* 3.56 is synthesized by reacting II-4 with 2-bromopropionyl bromide andthen performing a nucleophilic substitution with dimethylamine.

EXAMPLES 4 Reacting the Thiocarbamates with Amines and Alcohols

Preparing Ureas

0.17 mmol of amine and 30 μl of diisopropylethylamine are added to asolution of 0.11 mmol of thiocarbamate in 5 ml of ethanol and themixture is stirred at 80° C. for 15 h in a pressure tube. After thesolvent has been removed in vacuo, the residue is purifiedchromatographically.

Preparing Carbamates

5 ml of the appropriate alcohol are added to a solution of 0.11 mmol ofthiocarbamate (or methylcarbamate) and the mixture is stirred at 80° C.for 15 h in a pressure tube. After the solvent has been removed invacuo, the residue is purified chromatographically.

EXAMPLES 4.1-4.32

HPLC Rt [min] Starting Mass or m.p. # compound Structure [M + 1]⁺ orTLC:R_(f) 4.1 II-9

508 1.43 4.2 II-9

562 1.86 4.3 II-9

556 1.85 4.4 II-9

509 1.73 4.5 II-9

631 1.58 4.6 II-9

493 2.02 4.7 II-9

585 m.p.: 160° C. 4.8 II-9

562 1.59 4.9 II-9

630 1.68 4.10 II-9

549 1.65 4.11 II-9

551 R_(f) = 0.02 DCM:MeOH 9:1 4.12 II-9

565 R_(f) = 0.05 DCM:MeOH 9:1 4.13 II-9

520 1.43 4.14 II-9

534 1.54 4.15 II-9

550 1.43 4.16 II-9

563 1.3  4.17 II-9

576 1.83 4.18 II-9

574 1.79 4.19 II-9

562 1.42 4.20 II-9

508 1.49 4.21 II-9

548 1.68 4.22 2.176

460 1.43 4.23 2.176

488 1.45 4.24 2.177

685 1.49 4.25 2.177

721 1.55 4.26 2.178

508 1.58 4.27 I-43

437 1.59 4.28 I-44

551 m.p.: 199° C. 4.29 I-44

439 m.p.: 273° C. 4.30 I-44

538 m.p.: 220° C. 4.31 I-43

551 1.94 4.32 I-1

466 3.61

EXAMPLES 5 Reacting the Chloropyridyl Building Blocks

Synthesis Method H

If the amines are present in liquid form, 0.2 mmol of the chloropyridinebuilding block is dissolved in 0.5 ml of amine and the solution isheated at 120° C. for 10 min in a microwave (CEM). After the excessamine has been removed, the residue is purified chromatographically.

Synthesis Method I

A solution of 1.2 mmol of chloropyridine building block and 3 mmol ofamine in 3 ml of N-methylpyrrolidinone, DMSO or DMF is heated at 120° C.for 10 min in a microwave (CEM). After the solvent and the excess aminehave been removed, the residue is purified chromatographically.

EXAMPLES 5.1-5.23

HPLC Rt [min] Starting Mass or m.p. # compound Structure [M + 1]⁺ orTLC:R_(f) 5.1 I-3

463 1.67 5.2 I-3

421 1.44 5.3 I-14

462 0.3  5.4 I-14

488 0.28 5.5 I-14

476 1.5  5.6 I-14

488 1.34 5.7 I-14

487 1.35 5.8 I-14

500 1.89 5.9* I-14

487 1.16 5.9b I-14

445 R_(f) = 0.02 DCM:MeOH 9:1 5.10 I-14

432 1.26 5.11 I-14

444 1.31 5.12 I-14

474 1.52 5.13 I-14

541 2.93 5.14 I-14

515 2.78 5.15 I-14

489 1.26 5.16* I-14

564 R_(f) = 0.56 MeOH 5.16b I-15

522 1.13 5.17 I-15

458 R_(F) = 0.41 DCM:MeOH 8:2 5.18 I-15

472 1.36 5.19 I-14

503 R_(f) = 0.06 DCM:MeOH 9:1 5.20 I-14

501 R_(f) = 0.08 DCM:MeOH 9:1 5.21 I-14

531 1.17 5.22 I-14

555 1.28 5.23* I-14

472 3.35 5.23b I-14

430 3.12*Under the reaction conditions, the acetyl group is observed to beeliminated. The corresponding isolated free amine in Examples 5.9b,5.16b and 5.23b is reacetylated with acetic anhydride in dioxane.

EXAMPLES 6 Reductive Amination

Method J

A solution of 70 mg of II-10 (0.15 mmol) and 22 μl ofN-methylpiperidin-4-one (0.18 mmol) in 5 ml of dichloromethane isstirred at RT for 2 h. After 40 mg of sodium triacetoxyborohydride (0.18mmol) have been added, the reaction mixture is stirred for a further 15h. The mixture is diluted with dichloromethane and washed with a dilutesolution of sodium hydrogen carbonate; the organic phase is dried andevaporated. The residue is solubilized in a very small quantity of ethylacetate/methanol and crystallized using diethyl ether. The crystalswhich have precipitated out are filtered off and dried in vacuo.

Method K

A solution of 220 mg of II-11 (0.5 mmol) and 0.1 ml of benzylamine (1mmol) in 5 ml of methanol is stirred at 60° C. for 15 h after which 155mg of sodium triacetoxyborohydride (0.7 mmol) and 40 mg of sodiumacetate (0.5 mmol) are added. Following hydrolysis with sodium hydrogencarbonate and extraction with dichloromethane, the organic phase isdried and evaporated and the residue is purified chromatographically.

EXAMPLES 6.1-6.4

HPLC:Rt [min] Starting Mass or m.p. # compound Method Structure [M + 1]⁺or TLC:R_(f) 6.1 II-10 I

547 1.27 6.2 II-11 K

542 1.55 6.3 II-11 K

603 0.30 6.4 II-12 I

541 m.p.: 166° C.

Examples 7

Synthesis Method L—Crosscoupling with Arylboronic Acids

0.3 mmol of the appropriate boronic acid is added to a suspension of 100mg of I-24 (0.2 mmol) in 3 ml of acetone. 4.4 mg of palladium(II)acetate (19 μmol), 4 μl of diazabicyclooctane (39 μmol) and 80 mg ofpotassium carbonate are then added and the reaction vessel is heated at100° C. for 20 min in a microwave; after that, it is heated a further 2×for in each case 40 min at 120° C. and 70° C. After the solvent has beenremoved, the reaction mixture is purified chromatographically.

Synthesis Method M—Crosscoupling with Alkynes

56 mg of N,N-dimethylaminoprop-2-yne (0.7 mmol) anddiisopropylethylamine are added, while stirring and under an argonatmosphere, to a solution of 200 mg of I-31 (0.3 mmol), 6 mg ofcopper(I) iodide (34 μmol) and 24 mg of triphenylphosphinepalladium(II)chloride (34 μmol) in 25 ml of degassed THF and the reaction mixture isstirred at 80° C. for 15 h. 100 μl of alkyne, as well as 10 mg of Culand 20 mg of Pd catalyst, are added and the mixture is left to stir at55° C. for a further 24 h. The mixture is then made alkaline with anaqueous solution of NH₃, diluted with water and extracted 2× with THF.The combined organic phases are extracted by shaking with a saturatedsolution of NaCl, dried, filtered and evaporated. The residue ispurified chromatographically.

Synthesis Method N Palladium-Catalysed Amination

30 mg of tri-tert-butylphosphine tetrafluoroborate (0.1 mmol) are addedto a solution of 200 mg of I-31 (0.3 mmol), 38 mg of 4-aminopyridine(0.4 mmol), 47 mg of tris(dibenzylideneacetone)dipalladium (51 μmol) and111 mg of sodium tert-butoxide (1 mmol) in 4 ml of degassed DMF and themixture is stirred at 90° C. for 4 h under argon. Following hydrolysiswith phosphate buffer and water, the mixture is extracted withdichloromethane. The organic phase is dried, filtered and evaporated andthe residue is purified chromatographically.

EXAMPLES 7.1-7.8

Starting Mass HPLC Rt # compound Structure [M + 1]⁺ [min] 7.1 I-24

506 1.83 7.2 I-24

557 3.63 7.3 I-24

557 3.24 7.4 I-24

521 1.66 7.5 I-24

482 3.57 7.6 I-24

503 1.89 7.7 I-31

504 1.47 7.8 I-31

515 1.47

EXAMPLE 8

60 mg ofN-(3-hydrazinocarbonyl-1-phenyl-4,5-dihydro-1H-pyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-7-yl)-acetamide(0.16 mmol), which can be prepared from I-6 and hydrazine in accordancewith synthesis method B, are treated with 3 ml of triethyl orthoformateat 180° C. for 30 min in a microwave. After the excess ortho ester hasbeen removed in vacuo, the residue is purified chromatographically.Yield 4 mg

[M+1]⁺=379

Rt=1.75 min.

EXAMPLES 9.1-9.4

The following compounds are prepared in analogy with the synthesis ofExample II-2. Starting # compound Structure [M + 1]⁺ Rt [min] 9.1 I-34

402 1.63 9.2 I-33

436 1.67 9.3 I-32

402 1.56 9.4 I-35

436 1.66

The following example describes the biological effect of the compoundsaccording to the invention without limiting the invention to thisexample.

HCT116 Cytotoxicity Test

The test is based on the reduction of AlamarBlue (Biosource Int., USA)in living (metabolically active) cells to give a fluorometricallydetectable product. The substrate can no longer be reduced in thepresence of substances which are toxic to the cells, which means that itis not possible to measure any increase in fluorescence.

HCT116 (human colon carcinoma cell line) cells are sown in microtiterplates and incubated overnight in culture medium at 37° C. and 5% CO₂.The test substances are diluted stepwise in medium and added to thecells such that the total volume is 200 μl/well. Cells to which medium,but not substance, is added serve as controls. After an incubation timeof 4-6 days, 20 μl of AlamarBlue are added/well and the cells areincubated at 37° C. for a further 6-8 h. For measuring the fluorescence,excitation takes place at a wavelength of 545 nm and the emission ismeasured at 590 nm.

EC₅₀ values are calculated using the GraphPad Prism program.

All the examples cited have an EC₅₀ (HCT-116) of less than 5 μM.

The substances of the present invention are PI3 kinase inhibitors. Onaccount of their biological properties, the novel compounds of thegeneral formula (1) and their isomers and their physiologicallytolerated salts, are suitable for treating diseases which arecharacterized by excessive or anomalous cell proliferation.

These diseases include, for example: viral infections (e.g. HIV andKaposi's sarcoma); inflammation and autoimmune diseases (e.g. colitis,arthritis, Alzheimer's disease, glomerulonephritis and wound healing);bacterial, fungal and/or parasitic infections; leukaemias, lymphomas andsolid tumours; skin diseases (e.g. psoriasis); bone diseases;cardiovascular diseases (e.g. restenosis and hypertrophy). In addition,the compounds are useful for protecting proliferating cells (e.g. haircells, intestinal cells, blood cells and progenitor cells) from DNAdamage due to irradiation, UV treatment and/or cytostatic treatment(Davis et al., 2001).

For example, the following cancer diseases can be treated with compoundsaccording to the invention, without, however, being restricted thereto:brain tumours, such as acoustic neurinoma, astrocytomas such as piloidastrocytomas, fibrillary astrocytoma, protoplasmic astrocytoma,gemistocytic astrocytoma, anaplastic astrocytoma and glioblastomas,brain lymphomas, brain metastases, hypophyseal tumour such asprolactinoma, HGH (human growth hormone) producing tumour andACTH-producing tumour (adrenocorticotrophic hormone),craniopharyngiomas, medulloblastomas, meningiomas andoligodendrogliomas; nerve tumours (neoplasms) such as tumours of thevegetative nervous system such as neuroblastoma sympathicum,ganglioneuroma, paraganglioma (phaeochromocytoma and chromaffmoma) andglomus caroticum tumour, tumours in the peripheral nervous system suchas amputation neuroma, neurofibroma, neurinoma (neurilemoma, schwannoma)and malignant schwannoma, as well as tumours in the central nervoussystem such as brain and spinal cord tumours; intestinal cancer such asrectal carcinoma, colon carcinoma, anal carcinoma, small intestinetumours and duodenal tumours; eyelid tumours such as basalioma or basalcell carcinoma; pancreatic gland cancer or pancreatic carcinoma; bladdercancer or bladder carcinoma; lung cancer (bronchial carcinoma) such assmall-cell bronchial carcinomas (oat cell carcinomas) and non-small-cellbronchial carcinomas such as squamous epithelium carcinomas,adenocarcinomas and large-cell bronchial carcinomas; breast cancer suchas mammary carcinoma, such as infiltrating ductal carcinoma, colloidcarcinoma, lobular invasive carcinoma, tubular carcinoma, adenoid cysticcarcinoma, and papillary carcinoma; non-Hodgkin's lymphomas (NHL) suchas Burkitt's lymphoma, low-malignancy non-Hodkgin's lymphomas (NHL) andmucosis fungoides; uterine cancer or endometrial carcinoma or corpuscarcinoma; CUP syndrome (cancer of unknown primary); ovarian cancer orovarian carcinoma such as mucinous, endometrial or serous cancer; gallbladder cancer; bile duct cancer such as Klatskin's tumour; testicularcancer such as seminomas and non-seminomas; lymphoma (lymphosarcoma)such as malignant lymphoma, Hodgkin's disease, non-Hodgkin's lymphomas(NHL) such as chronic lymphatic leukaemia, hair cell leukaemia,immunocytoma, plasmocytoma (multiple myeloma), immunoblastoma, Burkitt'slymphoma, T-zone mycosis fungoides, large-cell anaplastic lymphoblastomaand lymphoblastoma; laryngeal cancer such as vocal cord tumours,supraglottal, glottal and subglottal laryngeal tumours; bone cancer suchas osteochondroma, chondroma, chrondoblastoma, chondromyxoidfibroma,osteoma, osteoid-osteoma, osteoblastoma, eosinophilic granuloma, giantcell tumour, chondrosarcoma, osteosarcoma, Ewing's sarcoma,reticulosarcoma, plasmocytoma, fibrous dysplasia, juvenile bone cyst andaneurysmatic bone cyst; head/neck tumours such as tumours of the lips,tongue, floor of the mouth, oral cavity, gingiva, pallet, salivaryglands, pharynx, nasal cavities, paranasal sinuses, larynx and middleear; liver cancer such as liver cell carcinoma or hepatocellularcarcinoma (HCC); leukaemias, such as acute leukaemias, such as acutelymphatic/lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML);chronic leukaemias such as chronic lymphatic leukaemia (CLL), chronicmyeloid leukaemia (CML); stomach cancer or stomach carcinoma such aspapillary, tubular and mucinous adenocarcinoma, signet ring cellcarcinoma, adenoid squamous cell carcinoma, small-cell carcinoma andundifferentiated carcinoma; melanomas such as superficially spreading,nodular malignant lentigo and acral lentiginous melanoma; renal cancer,such as kidney cell carcinoma or hypemephroma or Grawitz's tumour;oesophageal cancer or oesophageal carcinoma; cancer of the penis;prostate cancer; pharyngeal cancer or pharyngeal carcinomas such asnasopharyngeal carcinomas, oropharyngeal carcinomas and hypopharyngealcarcinomas; retinoblastoma; vaginal cancer or vaginal carcinoma;squamous epithelium carcinomas, adeno carcinomas, in situ carcinomas,malignant melanomas and sarcomas; thyroid gland carcinomas such aspapillary, follicular and medullary thyroid gland carcinoma, and alsoanaplastic carcinomas; spinalioma, prickle cell carcinoma and squamousepithelium carcinoma of the skin; thymomas, urethral cancer and vulvarcancer.

The novel compounds can be used for the prevention or short-term orlong-term treatment of the abovementioned diseases including, whereappropriate, in combination with other state-of-the-art compounds suchas other anti-tumour substances, cytotoxic substances,cell-proliferation inhibitors, antiangiogenic substances, steroids orantibodies.

The compounds of the general formula (1) can be used on their own or incombination with other active compounds according to the invention and,where appropriate, in combination with other pharmacologically activecompounds as well. Chemotherapeutic agents which can be administered incombination with the compounds according to the invention include,without being restricted thereto, hormones, hormone analogs andantihormones (e.g. tamoxifen, toremifene, raloxifene, fulvestrant,megestrol acetate, flutamide, nilutamide, bicalutamide,aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate,fludrocortisone, fluoxymesterone, medroxyprogesterone and octreotide),aromatase inhibitors (e.g. anastrozole, letrozole, liarozole, vorozole,exemestane and atamestane), LHRH agonists and antagonists (e.g.goserelin acetate and luprolide), inhibitors of growth factors (growthfactors such as platelet-derived growth factor and hepatocyte growthfactor, examples of inhibitors are growth factor antibodies, growthfactor receptor antibodies and tyrosine kinase inhibitors, such asgefitinib, imatinib, lapatinib and trastuzumab); antimetabolites (e.g.antifolates such as methotrexate and raltitrexed, pyrimidine analogssuch as 5-fluorouracil, capecitabine and gemcitabine, purine andadenosine analogs such as mercaptopurine, thioguanine, cladribine andpentostatin, cytarabine and fludarabine); antitumour antibiotics (e.g.anthracyclines, such as doxorubicin, daunorubicin, epirubicin andidarubicin, mitomycin C, bleomycin, dactinomycin, plicamycin andstreptozocin); platinum derivatives (e.g. cisplatin, oxaliplatin andcarboplatin); alkylating agents (e.g. estramustine, meclorethamine,melphalan, chlorambucil, busulphan, dacarbazine, cyclophosphamide,ifosfamide and temozolomide, nitrosoureas such as carmustine andlomustine and thiotepa); antimitotic agents (e.g. vinca alkaloids suchas vinblastine, vindesine, vinorelbine and vincristine; and taxans suchas paclitaxel and docetaxel); topoisomerase inhibitors (e.g.epipodophyllotoxins such as etoposide and etopophos, teniposide,amsacrine, topotecan, irinotecan and mitoxantrone) and variouschemotherapeutic agents such as amifostin, anagrelide, clodronate,filgrastin, interferon alpha, leucovorin, rituximab, procarbazine,levamisole, mesna, mitotan, pamidronate and porfimer.

Examples of suitable forms for use are tablets, capsules, suppositories,solutions, in particular solutions for injection (s.c., i.v., i.m.) andinfusion, juices, emulsions or dispersible powders. In this connection,the proportion of the pharmaceutically active compound(s) should in eachcase be in the range of 0.1-90% by weight, preferably 0.5-50% by weight,of the total composition, that is in quantities which are sufficient toachieve the dosage range which is specified below. If necessary, thedoses mentioned can be given several times a day.

Appropriate tablets can be obtained, for example, by mixing the activecompound(s) with known auxiliary substances, for example inert diluents,such as calcium carbonate, calcium phosphate or lactose, disintegrants,such as maize starch or alginic acid, binders, such as starch orgelatine, lubricants, such as magnesium stearate or talc, and/or agentsfor achieving a depot effect, such as carboxymethyl cellulose, celluloseacetate phthalate or polyvinyl acetate. The tablets can also compriseseveral layers.

Correspondingly, sugar-coated tablets can be produced by coating cores,which have been prepared in analogy with tablets, with agents which arecustomarily used in sugar coatings, for example collidone or shellac,gum arabic, talc, titanium dioxide or sugar. The core can also compriseseveral layers in order to achieve a depot effect or to avoidincompatibilities. In the same way, the sugar coating can also compriseseveral layers in order to achieve a depot effect, with it beingpossible to use the auxiliary substances which are mentioned above inthe case of the tablets.

Juices of the active compounds or active compound combinations accordingto the invention can additionally comprise a sweetening agent, such assaccharine, cyclamate, glycerol or sugar as well as a taste-improvingagent, e.g. flavouring agents such as vanillin or orange extract. Theycan also comprise suspension aids or thickeners, such as sodiumcarboxymethyl cellulose, wetting agents, for example condensationproducts of fatty alcohols and ethylene oxide, or protectants such asp-hydroxybenzoates.

Injection and infusion solutions are produced in a customary manner,e.g. while adding isotonizing agents, preservatives, such asp-hydroxybenzoates, or stabilizers, such as alkali metal salts ofethylenediaminetetraacetic acid, where appropriate using emulsifiersand/or dispersants, with it being possible, for example, to employ,where appropriate, organic solvents as solubilizing agents or auxiliarysolvents when using water as diluent, and aliquoted into injectionbottles or ampoules or infusion bottles.

The capsules, which comprise one or more active compounds or activecompound combinations, can, for example, be produced by mixing theactive compounds with inert carriers, such as lactose or sorbitol, andencapsulating the mixture in gelatine capsules. Suitable suppositoriescan be produced, for example, by mixing with excipients which areenvisaged for this purpose, such as neutral fats or polyethylene glycol,or their derivatives.

Auxiliary substances which may be mentioned by way of example are water,pharmaceutically unobjectionable organic solvents, such as paraffins(e.g. petroleum fractions), oils of vegetable origin (e.g. groundnut oilor sesame oil), monofunctional or polyfunctional alcohols (e.g. ethanolor glycerol), carrier substances such as natural mineral powders (e.g.kaolins, argillaceous earths, talc and chalk), synthetic mineral powders(e.g. highly disperse silicic acid and silicates), sugars (e.g. canesugar, lactose and grape sugar), emulsifiers (e.g. lignin, sulphitewaste liquors, methyl cellulose, starch and polyvinylpyrrolidone) andglidants (e.g. magnesium stearate, talc, stearic acid and sodium laurylsulphate).

Administration is effected in a customary manner, preferably orally ortransdermally, in particular and preferably orally. In the case of oraluse, the tablets can naturally also comprise, in addition to theabovementioned carrier substances, additives such as sodium citrate,calcium carbonate and dicalcium phosphate together with a variety offurther substances such as starch, preferably potato starch, gelatineand the like. It is furthermore also possible to use glidants, such asmagnesium stearate, sodium lauryl sulphate and talc, for the tableting.In the case of aqueous suspensions, a variety of taste improvers or dyescan also be added to the active compounds in addition to theabovementioned auxiliary substances.

For parenteral administration, it is possible to employ solutions of theactive compounds while using suitable liquid carrier materials. Thedosage for intravenous administration is 1-1000 mg per hour, preferablybetween 5 and 500 mg per hour.

Despite this, it may be necessary, where appropriate, to diverge fromthe abovementioned quantities, depending on the body weight or thenature of the route of administration, on the individual response to themedicament, on the nature of its formulation and on the time or intervalat which the administration is effected. Thus, it may, in some cases, besufficient to make do with less than the previously mentioned lowestquantity whereas, in other cases, the abovementioned upper limit has tobe exceeded. When relatively large quantities are being administered, itmay be advisable to divide these into several single doses which aregiven over the course of the day.

The following formulation examples illustrate the present inventionwithout, however, restricting its scope:

Pharmaceutical Formulation Examples A) Tablets per tablet Activecompound in accordance with formula (1) 100 mg Lactose 140 mg Maizestarch 240 mg Polyvinylpyrrolidone  15 mg Magnesium stearate  5 mg 500mg

The finely ground active compound, lactose and a part of the maizestarch are mixed with each other. The mixture is sieved, after which itis moistened with a solution of polyvinylpyrrolidone in water, kneaded,wet-granulated and dried. The granular material, the remainder of themaize starch and the magnesium stearate are sieved and mixed with eachother. The mixture is pressed into tablets of suitable shape and size.B) Tablets per tablet Active compound in accordance with formula (1) 80mg Lactose 55 mg Maize starch 190 mg  Microcrystalline cellulose 35 mgPolyvinylpyrrolidone 15 mg Sodium carboxymethyl starch 23 mg Magnesiumstearate  2 mg 400 mg 

The finely ground active compound, a part of the maize starch, thelactose, microcrystalline cellulose and polyvinylpyrrolidone are mixedwith each other, after which the mixture is sieved and worked, togetherwith the remainder of the maize starch and water, into a granularmaterial, which is dried and sieved. The sodium carboxymethyl starch andthe magnesium stearate are then added to the granular material and mixedwith it, and the mixture is pressed into tablets of suitable size. C)Ampoule solution Active compound in accordance with formula (1) 50 mgSodium chloride 50 mg Water for injection  5 ml

The active compound is dissolved, either at its intrinsic pH or, whereappropriate, at pH 5.5-6.5, in water after which sodium chloride isadded as isotonizing agent. The resulting solution is renderedpyrogen-free by filtration and the filtrate is aliquoted, under asepticconditions, into ampoules, which are then sterilized and sealed bymelting. The ampoules contain 5 mg, 25 mg and 50 mg of active compound.

1.) A compound of formula (1),

in which R¹ is selected from the group consisting of —NHR^(c), —NHC(O)R^(c), —NHC(O)OR^(c), —NHC(O)NR^(c)R^(c) and —NHC(O)SR^(c); R² is a radical which is optionally substituted by one or more R⁴ and which is selected from the group consisting of C₁₋₆alkyl, C₃₋₈cycloalkyl, 3-8-membered heterocycloalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl and 5-10-membered heteroaryl; R³ is a radical which is optionally substituted by one or more R^(e) and/or R^(f) and is selected from the group consisting of C₆₋₁₀aryl and 5-10-membered heteroaryl; R⁴ is a radical selected from the group consisting of R^(a), R^(b) and R^(a) which is substituted by one or more, identical or different, R^(c) and/or R^(b); each R^(a) is, independently of each other, selected from the group consisting of C₁₋₆alkyl, C₃₋₈cycloalkyl, C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6-membered heteroalkyl, 3-8-membered heterocycloalkyl, 4-14-membered heterocycloalkylalkyl, 5-10-membered heteroaryl and 6-16-membered heteroarylalkyl; each R^(b) is a suitable radical and in each case selected, independently of each other, from the group consisting of ═O, —OR^(c), C₁₋₃haloalkyloxy, —OCF₃, ═S, —SR^(c), ═NR^(c), ═NOR^(c), —NR^(c)R^(c), halogen, —CF3, —CN, —NC, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(c), —S(O)₂R^(c), —S(O)₂OR^(c), —S(O)NR^(c)R^(c), —S(O)₂NR^(c)R^(c), —OS(O)R^(c), —OS(O)₂R^(c), —OS(O)₂OR^(c), —OS(O)₂NR^(c)R^(c), —C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(c), —C(O)N(R^(g))NR^(c)R^(c), —C(O)N(R^(g))OR^(c), —CN(R^(g))NR^(c)R^(c), —OC(O)R^(c), —OC(O)OR^(c), —OC(O)NR²R², —OCN(R^(g))NR^(c)R^(c), —N(R^(g))C(O)R^(c), —N(R^(g))C(O)R^(c), —N(R^(g))C(S)R^(c), —N(R^(g))S(O)₂R^(c), —N(R^(g))S(O)₂NR^(c)R^(c), —N[S(O)₂]₂R^(c), —N(R^(g))C(O)OR^(c), —N(R^(g))C(O)NR^(c)R^(c), and —N(R^(g))CN(R^(g))NR^(c)R^(c); each R^(c) is, independently of each other, hydrogen or a radical which is optionally substituted by one or more, identical or different, R^(d) and/or R^(e) and which is selected from the group consisting of C₁₋₆alkyl, C₃₋₈cycloalkyl, C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6-membered heteroalkyl, 3-8-membered heterocycloalkyl, 4-14-membered heterocycloalkylalkyl, 5-10-membered heteroaryl and 6-16-membered heteroarylalkyl, each R^(d) is, independently of each other, hydrogen or a radical which is optionally substituted by one or more, identical or different, R^(e) and/or R^(f) and which is selected from the group consisting of C₁₋₆alkyl, C₃₋₈cycloalkyl, C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6-membered heteroalkyl, 3-8-membered heterocycloalkyl, 4-14-membered heterocycloalkylalkyl, 5-10-membered heteroaryl and 6-16-membered heteroarylalkyl, each R^(e) is a suitable radical and in each case selected, independently of each other, from the group consisting of ═O, —OR^(f), C₁₋₃haloalkyloxy, —OCF₃, ═S, —SR^(f), ═NR^(f), ═NOR^(f), —NR^(f)R^(f), halogen, —CF3, —CN, —NC, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(f), —S(O)₂R^(f), —S(O)₂OR^(f), —S(O)NR^(f)R^(f), —S(O)₂NR^(f)R^(f), —OS(O)R^(f), —OS(O)₂R^(f), —OS(O)₂OR^(f), —OS(O)₂NR^(f)R^(f), —C(O)R^(f), —C(O)OR^(f), —C(O)NR^(f)R^(f), —CN(R^(g))NR^(f)R^(f), —OC(O)R^(f), —OC(O)OR^(f), —OC(O)NR^(f)R^(f), —OCN(R^(g))NR^(f)R^(f), —N(R^(g))C(O)R^(f), —N(R^(g))C(S)R^(f), —N(R^(g))S(O)₂R^(f), —N(R^(g))C(O)OR^(f), —N(R^(g))C(O)NR^(f)R^(f), and —N(R^(g))CN(R^(g))NR^(f)R^(f); each R^(f) is, independently of each other, hydrogen or a radical which is optionally substituted by one or more, identical or different, R^(g) and is selected from the group consisting of C₁₋₆alkyl, C₃₋₈cycloalkyl, C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6-membered heteroalkyl, 3-8-membered heterocycloalkyl, 4-14-membered heterocycloalkylalkyl, 5-10-membered heteroaryl and 6-16-membered heteroarylalkyl, each R^(g) is, independently of each other, hydrogen, C₁₋₆alkyl, C₃₋₈cycloalkyl, C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋ ₁₆arylalkyl, 2-6-membered heteroalkyl, 3-8-membered heterocycloalkyl, 4-14-membered heterocycloalkylalkyl, 5-10-membered heteroaryl and 6-16-membered heteroarylalkyl, or a pharmaceutically acceptable acid addition salt thereof. 2.) The compound according to claim 1, wherein R³ is a radical selected from the group consisting of phenyl, furyl, pyridyl, pyrimidinyl and pyrazinyl, optionally substituted by one or more R⁴. 3.) The compound according to claim 2, wherein R³ is pyridyl. 4.) The compound according to claim 1, wherein R¹ is —NHC(O)R^(c). 5.) The compound according to claim 4, wherein R¹ is —NHC(O)CH₃. 6.) A compound of formula (A)

wherein X is —CH₃, —OR⁴ or —SR⁴ and Y is phenyl, 5-10-membered heteroaryl or the group —C(O)O, and R^(y) is hydrogen, —NO₂ or C₁₋₆alkyl and R⁴ is a radical selected from the group consisting of R^(a), R^(b) and R^(a) which is substituted by one or more, identical or different, R^(c) and/or R^(b); each R^(a) is, independently of each other, selected from the group consisting of C₁₋₆alkyl, C₃₋₈cycloalkyl, C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋ ₁₆arylalkyl, 2-6-membered heteroalkyl, 3-8-membered heterocycloalkyl, 4-14-membered heterocycloalkylalkyl, 5-10-membered heteroaryl and 6-16-membered heteroarylalkyl; each R^(b) is a suitable radical and in each case selected, independently of each other, from the group consisting of ═O, —OR^(c), C₁₋₃haloalkyloxy, —OCF₃, ═S, —SRC, ═NR^(c), ═NOR^(c), —NR^(c)R^(c), halogen, —CF3, —CN, —NC, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(c), —S(O)₂R^(c), —S(O)₂OR^(c), —S(O)NR^(c)R^(c), —S(O)₂NR^(c)R^(c), —OS(O)R^(c), —OS(O)₂R^(c), —OS(O)₂OR^(c), —OS(O)₂NR^(c)R^(c), —C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(c), —C(O)N(R^(g))NR^(c)R^(c), —C(O)N(R^(g))OR^(c), —CN(R^(g))NR^(c)R^(c), —OC(O)R^(c), —OC(O)OR^(c), —OC(O)NR^(c)R^(c), —OCN(R^(g))NR^(c)R^(c), —N(R^(g))C(O)R^(c), —N(R^(g))C(O)R^(c), —N(R^(g))C(S)R^(c), —N(R^(g))S(O)₂R^(c), —N(R^(g))S(O)₂NR^(c)R^(c), —N[S(O)₂]₂R^(c), —N(R^(g))C(O)OR^(c), —N(R^(g))C(O)NR^(c)R^(c), and —N(R^(g))CN(R^(g))NR^(c)R^(c); each R^(c) is, independently of each other, hydrogen or a radical which is optionally substituted by one or more, identical or different, R^(d) and/or R^(e) and which is selected from the group consisting of C₁₋₆alkyl, C₃₋₈cycloalkyl, C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6-membered heteroalkyl, 3-8-membered heterocycloalkyl, 4-14-membered heterocycloalkylalkyl, 5-10-membered heteroaryl and 6-16-membered heteroarylalkyl, each R^(d) is, independently of each other, hydrogen or a radical which is optionally substituted by one or more, identical or different, R^(e) and/or R^(f) and which is selected from the group consisting of C₁₋₆alkyl, C₃₋₈cycloalkyl, C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6-membered heteroalkyl, 3-8-membered heterocycloalkyl, 4-14-membered heterocycloalkylalkyl, 5-10-membered heteroaryl and 6-16-membered heteroarylalkyl, each R^(e) is a suitable radical and in each case selected, independently of each other, from the group consisting of ═O, —OR^(f), C₁₋₃haloalkyloxy, —OCF₃, ═S, —SR^(f), ═NR^(f), ═NOR^(f), —NR^(f)R^(f), halogen, —CF3, —CN, —NC, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(f), —S(O)₂R^(f), —S(O)₂OR^(f), —S(O)NR^(f)R^(f), —S(O)₂NR^(f)R^(f), —OS(O)R^(f), —OS(O)₂R^(f), —OS(O)₂OR^(f), —OS(O)₂NR^(f)R^(f), —C(O)R^(f), —C(O)OR^(f), —C(O)NR^(f)R^(f), —CN(R^(g))NR^(f)R^(f), —OC(O)R^(f), —OC(O)OR^(f), —OC(O)NR^(f)R^(f), —OCN(R^(g))NR^(f)R^(f), —N(R^(g))C(O)R^(f), —N(R^(g))C(S)R^(f), —N(R^(g))S(O)₂R^(f), —N(R^(g))C(O)OR^(f), —N(R^(g))C(O)NR^(f)R^(f), and —N(R^(g))CN(R^(g))NR^(f)R^(f); each R^(f) is, independently of each other, hydrogen or a radical which is optionally substituted by one or more, identical or different, R^(g) and is selected from the group consisting of C₁₋₆alkyl, C₃₋₈cycloalkyl, C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6-membered heteroalkyl, 3-8-membered heterocycloalkyl, 4-14-membered heterocycloalkylalkyl, 5-10-membered heteroaryl and 6-16-membered heteroarylalkyl, each R^(g) is, independently of each other, hydrogen, C₁₋₆alkyl, C₃₋₈cycloalkyl, C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6-membered heteroalkyl, 3-8-membered heterocycloalkyl, 4-14-membered heterocycloalkylalkyl, 5-10-membered heteroaryl and 6-1 6-membered heteroarylalkyl, or a pharmaceutically acceptable acid addition salt thereof. 7.) The compound according to claim 6, wherein R⁴ is —C₁₋₆alkyl. 8.) A pharmaceutical preparation which comprises, as active compound, one or more compounds of the formula (1) according to claim 1, in combination with customary auxiliary substances and/or carrier substances. 9.) A pharmaceutical preparation which comprises a compound of the formula (1) according to claim 1 and at least one further cytostatic or cytotoxic active substance which differs from such compound according to claim
 1. 10.) A method for producing an anti-proliferative effect in a warm-blooded animal which may be useful in the treatment of cancer and other disorders of cell growth which comprises administering to the animal a therapeutically effective amount of a compound of formula (1) according to claim
 1. 